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Yu S, Si Y, Xu M, Wang Y, Liu C, Bi C, Sun M, Sun H. Downregulation of the splicing regulator NSRP1 confers resistance to CDK4/6 inhibitors via activation of interferon signaling in breast cancer. J Biol Chem 2025; 301:108070. [PMID: 39667501 PMCID: PMC11750474 DOI: 10.1016/j.jbc.2024.108070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Revised: 11/16/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024] Open
Abstract
The combination of CDK4/6 inhibitors (CDK4/6i) and endocrine therapy is the first-line therapy for ER+/Her2-breast cancer; however, the development of drug resistance limited the efficacy of the agents. Although activation of the IFN signaling pathway has been identified as a critical driver of intrinsic and acquired CDK4/6i resistance, it remains unknown how the IFN signaling pathway was activated in resistant cells. Here, we report that NSRP1, a regulator of alternative mRNA splicing is downregulated in CDK4/6i resistant breast cancer cells and contributes to CDK4/6i resistance by mediating alternative splicing of NSD2 mRNA and activation of the IFN signaling pathway. Knockdown of NSRP1 reduces CDK4/6i (palbociclib) sensitivity of MCF7 cells while overexpression of NSRP1 sensitizes MCF7-PalR cells towards palbociclib treatment. Mechanistically, RNA sequencing suggests that NSRP1 knockdown strongly activates the IFN signaling pathway in MCF7 cells and elevates the expression of most of the "IFN-related palbociclib-resistance Signature" (IRPS) genes. NSRP1 also regulates numerous alternative splicing (AS) events in breast cancer cells, several of which are key regulators of the IFN signaling pathway. Among them, the inclusion of NSD2 exon 2 is elevated upon NSRP1 knockdown. Our data further show that the inclusion of NSD2 exon 2 is increased in breast cancer and associated with the poor prognosis of patients. In addition, including NSD2 exon 2 elevates NSD2 protein expression to activate the IFN signaling pathway. This study unveils the critical role of NSRP1 in regulating the IFN signaling pathway and the CDK4/6i resistance, which could be a promising biomarker for predicting therapy response.
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Affiliation(s)
- Shiyi Yu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China
| | - Yue Si
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China
| | - Miao Xu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China
| | - Ying Wang
- Department of Thyroid and Breast Surgery, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, China
| | - Chengxu Liu
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China
| | - Caili Bi
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China
| | - Maoqiu Sun
- Department of Obstetrics and Gynecology, Haian Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nantong, Jiangsu, China.
| | - Haibo Sun
- Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu, China; Jiangsu Key Laboratory of Experimental & Translational Non-Coding RNA Research, Yangzhou University, Yangzhou, Jiangsu, China.
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Gui Z, Shi W, Zhou F, Yan Y, Li Y, Xu Y. The role of estrogen receptors in intracellular estrogen signaling pathways, an overview. J Steroid Biochem Mol Biol 2025; 245:106632. [PMID: 39551163 DOI: 10.1016/j.jsbmb.2024.106632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/29/2024] [Accepted: 11/09/2024] [Indexed: 11/19/2024]
Abstract
To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca2+ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell's function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.
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Affiliation(s)
- Zichang Gui
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China.
| | - Wei Shi
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Fangting Zhou
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yongqing Yan
- Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
| | - Yuntian Li
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yang Xu
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China; Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
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3
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Cloutier G, Beaulieu JF. Reconsideration of the laminin receptor 67LR in colorectal cancer cells. BIOMOLECULES & BIOMEDICINE 2024; 24:1117-1132. [PMID: 38606907 PMCID: PMC11378999 DOI: 10.17305/bb.2024.10323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/04/2024] [Accepted: 04/04/2024] [Indexed: 04/13/2024]
Abstract
The 67 kDa laminin receptor (67LR) was identified as the first laminin receptor shown to be involved in the carcinogenesis of various cancers, including colorectal cancer. While the exact composition of this 67 kDa receptor remains unknown, it has been reported to be formed by the 37 kDa ribosomal protein SA (RPSA) covalently attached to another unidentified protein. The goal of this study was to clarify the molecular structure of 67LR to enhance our understanding of its role in malignancies. Using cell fractionation of colorectal cancer cells, the 67 kDa immunoreactive protein corresponding to 67LR was found in the soluble protein fraction, while some of the 37 kDa RPSA exhibited plasma membrane-like properties. Proteomic analysis of the 67 kDa fraction revealed the absence of RPSA but identified the β-galactosidase-related 67 kDa elastin-binding protein (67EBP), another laminin binding receptor which presents amino acid sequence similarities that can explain the immune cross reactivity with RPSA. The downregulation of β-galactosidase through short hairpin RNA (shRNA) led to a reduction in both 67LR and 67EBP immunoreactive proteins, confirming the misidentification of 67LR and 67EBP in colorectal cancer cells. Based on these findings, we propose to redefine the 67LR as the RPSA-containing laminin receptor (RCLR) to avoid confusion with the 67EBP.
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Affiliation(s)
- Gabriel Cloutier
- Department of Immunology and Cell Biology, Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
| | - Jean-François Beaulieu
- Department of Immunology and Cell Biology, Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada
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4
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Valentín López JC, Lange CA, Dehm SM. Androgen receptor and estrogen receptor variants in prostate and breast cancers. J Steroid Biochem Mol Biol 2024; 241:106522. [PMID: 38641298 PMCID: PMC11139604 DOI: 10.1016/j.jsbmb.2024.106522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 03/23/2024] [Accepted: 04/14/2024] [Indexed: 04/21/2024]
Abstract
The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.
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Affiliation(s)
| | - Carol A Lange
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Medicine-Hematology, Oncology & Transplantation, University of Minnesota, Minneapolis, MN, USA
| | - Scott M Dehm
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA; Department of Urology, University of Minnesota, Minneapolis, MN, USA.
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5
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Hancock GR, Gertz J, Jeselsohn R, Fanning SW. Estrogen Receptor Alpha Mutations, Truncations, Heterodimers, and Therapies. Endocrinology 2024; 165:bqae051. [PMID: 38643482 PMCID: PMC11075793 DOI: 10.1210/endocr/bqae051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 04/02/2024] [Accepted: 04/17/2024] [Indexed: 04/23/2024]
Abstract
Annual breast cancer (BCa) deaths have declined since its apex in 1989 concomitant with widespread adoption of hormone therapies that target estrogen receptor alpha (ERα), the prominent nuclear receptor expressed in ∼80% of BCa. However, up to ∼50% of patients who are ER+ with high-risk disease experience post endocrine therapy relapse and metastasis to distant organs. The vast majority of BCa mortality occurs in this setting, highlighting the inadequacy of current therapies. Genomic abnormalities to ESR1, the gene encoding ERα, emerge under prolonged selective pressure to enable endocrine therapy resistance. These genetic lesions include focal gene amplifications, hotspot missense mutations in the ligand binding domain, truncations, fusions, and complex interactions with other nuclear receptors. Tumor cells utilize aberrant ERα activity to proliferate, spread, and evade therapy in BCa as well as other cancers. Cutting edge studies on ERα structural and transcriptional relationships are being harnessed to produce new therapies that have shown benefits in patients with ESR1 hotspot mutations. In this review we discuss the history of ERα, current research unlocking unknown aspects of ERα signaling including the structural basis for receptor antagonism, and future directions of ESR1 investigation. In addition, we discuss the development of endocrine therapies from their inception to present day and survey new avenues of drug development to improve pharmaceutical profiles, targeting, and efficacy.
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Affiliation(s)
- Govinda R Hancock
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
| | - Jason Gertz
- Department of Oncological Sciences, Huntsman Cancer Center, University of Utah, Salt Lake City, UT 84112, USA
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
- Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
| | - Sean W Fanning
- Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60513, USA
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6
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Kranjčević JK, Čonkaš J, Ozretić P. The Role of Estrogen and Estrogen Receptors in Head and Neck Tumors. Cancers (Basel) 2024; 16:1575. [PMID: 38672656 PMCID: PMC11049451 DOI: 10.3390/cancers16081575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 04/12/2024] [Accepted: 04/18/2024] [Indexed: 04/21/2024] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the most common histological form of head and neck tumors (HNTs), which originate from the epithelium of the lips and oral cavity, pharynx, larynx, salivary glands, nasal cavity, and sinuses. The main risk factors include consumption of tobacco in all forms and alcohol, as well as infections with high-risk human papillomaviruses or the Epstein-Barr virus. Regardless of the etiological agent, the risk of developing different types of HNTs is from two to more than six times higher in males than in females. The reason for such disparities probably lies in a combination of both biological and psychosocial factors. Therefore, it is hypothesized that exposure to female sex hormones, primarily estrogen, provides women with protection against the formation and metastasis of HNTs. In this review, we synthesized available knowledge on the role of estrogen and estrogen receptors (ERs) in the development and progression of HNTs, with special emphasis on membrane ERs, which are much less studied. We can summarize that in addition to epidemiologic studies unequivocally pointing to the protective effect of estrogen in women, an increased expression of both nuclear ERs, ERα, and ERβ, and membrane ERs, ERα36, GPER1, and NaV1.2, was present in different types of HNSCC, for which anti-estrogens could be used as an effective therapeutic approach.
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Affiliation(s)
| | | | - Petar Ozretić
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia (J.Č.)
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7
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Wu G, Qi G, Liu Y, Gan J, Xie C, Wu Q, Cui W, Wang C, Wang Z. ER-α36 is involved in calycosin inhibition of IL-6 production in macrophages. J Cell Mol Med 2024; 28:e18037. [PMID: 37974543 PMCID: PMC10805506 DOI: 10.1111/jcmm.18037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 10/15/2023] [Accepted: 10/18/2023] [Indexed: 11/19/2023] Open
Abstract
The tumour microenvironment (TME) is crucial for tumour development and progression. Tumour-associated macrophages (TAMs) in the TME can promote tumour progression and metastasis by releasing cytokines, such as IL-6. Calycosin, a phytoestrogen that is one of the active compounds in Radix Astragali, has been shown to inhibit tumour growth and metastasis. However, the underlying mechanism by which calycosin inhibits tumour growth remains unclear. Thus, this study aimed to investigate the effect of calycosin on IL-6 production in peripheral blood mononuclear cell (PBMC)- and THP-1-derived macrophages and explore its potential mechanisms using co-immunoprecipitation, western blotting, immunofluorescence, chromatin immunoprecipitation and luciferase assays. We found that calycosin treatment substantially upregulated the expression of ER-α36, a variant of the ER, and reduced IL-6 production in macrophages. Mechanistically, ER-α36 physically interacted with NF-κBp65 and retained p65 in the cytoplasm to attenuate NF-κB function as an IL-6 transcriptional inducer. In conclusion, our result indicated that calycosin inhibited IL-6 production by enhancing ER-α36 expression and its interaction with p65, which attenuated NF-κB function as an IL-6 inducer. Therefore, calycosin can be developed as an effective agent for cancer therapy by targeting TAMs.
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Affiliation(s)
- Guoli Wu
- Xiangya HospitalCentral South UniversityChangshaChina
| | - Guangying Qi
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Yu Liu
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Jinfeng Gan
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Chichu Xie
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Qi Wu
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Wei Cui
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Chunhua Wang
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
| | - Zhaoyi Wang
- Guangxi Key Laboratory of Tumor Immunology and Microenvironment Regulation, Department of Basic MedicineGuilin Medical UniversityGuilinChina
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8
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Adewumi AT, Mosebi S. Characteristic Binding Landscape of Estrogen Receptor-α36 Protein Enhances Promising Cancer Drug Design. Biomolecules 2023; 13:1798. [PMID: 38136668 PMCID: PMC10741999 DOI: 10.3390/biom13121798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/01/2023] [Accepted: 12/05/2023] [Indexed: 12/24/2023] Open
Abstract
Breast cancer (BC) remains the most common cancer among women worldwide, and estrogen receptor-α expression is a critical diagnostic factor for BC. Estrogen receptor (ER-α36) is a dominant-negative effector of ER-α66-mediated estrogen-responsive gene pathways. ER-α36 is a novel target that mediates the non-genomic estrogen signaling pathway. However, the crystallized structure of ER-α36 remains unavailable for molecular studies. ER-positive and triple-negative BC tumors aggressively resist the FDA-approved drugs; therefore, highly potent structure-based inhibitors with preeminent benefits over toxicity will preferably replace the current BC treatment. Broussoflanol B (BFB), a B. papyrifera bark compound, exhibits potent growth inhibitory activity in ER-negative BC cells by inducing cell cycle arrest. For the first time, we unravel the comparative dynamic events of the enzymes' structures and the binding mechanisms of BFB when bound to the ER-α36 and ER-α66 ligand-binding domain using an all-atom molecular dynamics simulations approach and MM/PBSA-binding-free energy calculations. The dynamic findings have revealed that ER-α36 and ER-α66 LBD undergo timescale "coiling", opening and closing conformations favoring the high-affinity BFB-bound ER-α36 (ΔG = -52.57 kcal/mol) compared to the BFB-bound ER-α66 (ΔG = -42.41 kcal/mol). Moreover, the unbound (1.260 Å) and bound ER-α36 (1.182 Å) exhibit the highest flexibilities and atomistic motions relative to the ER-α66 systems. The RMSF (Å) of the unbound ER-α36 and ER-α66 exhibit lesser stabilities than the BFB-bound systems, resulting in higher structural flexibilities and atomistic motions than the bound variants. These findings present a model that describes the mechanisms by which the BFB compound induces downregulation-accompanied cell cycle arrest at the Gap0 and Gap1 phases.
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Affiliation(s)
| | - Salerwe Mosebi
- Department of Life and Consumer Sciences, University of South Africa, Private Bag X06, Florida 1710, South Africa;
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9
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Ishii H, Hattori Y, Ozawa H. Estrogen Receptor α Isoforms Generated by Alternative Use of Cryptic Exons. J NIPPON MED SCH 2023; 90:364-371. [PMID: 37558429 DOI: 10.1272/jnms.jnms.2023_90-507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/11/2023]
Abstract
Estrogen receptor α (ERα) regulates several physiological functions. In pathophysiological conditions, ERα is involved in the development and progression of estrogen-sensitive tumors. The ERα gene contains multiple 5'-untranslated exons and eight conventional coding exons and presents multiple isoforms generated by alternative promoter usage and alternative splicing. This gene also possesses non-conventional exons in the 3'- and intronic regions, and alternative use of cryptic exons contributes to further diversity of ERα mRNAs and proteins. Recently, the genomic organization of ERα genes and the splicing profiles of their transcripts were comparatively analyzed in humans, mice, and rats, and multiple ERα isoforms with distinct structures and functions were identified. These transcripts contain cryptic sequences that encode insertion-containing or truncated ERα proteins. In particular, alternative cryptic exons with in-frame stop codons yield transcripts encoding C-terminally-truncated ERα proteins. The C-terminally-truncated ERα isoforms lack part or all of the ligand-binding domain but possess an isoform-specific sequence. Some of these isoforms exhibit constitutive transactivation and resistance to estrogen receptor antagonists. Although numerous studies have reported conflicting results regarding their functions, the critical determinant for their gain-of-function has been identified structurally. Here we review recent progress in ERα variant research concerning the genomic organization of ERα genes, splicing profiles of ERα transcripts, and transactivation properties of ERα isoforms.
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Affiliation(s)
- Hirotaka Ishii
- Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School
| | - Yujiro Hattori
- Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School
| | - Hitoshi Ozawa
- Department of Anatomy and Neurobiology, Graduate School of Medicine, Nippon Medical School
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10
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Al-Kabariti AY, Abbas MA. Progress in the Understanding of Estrogen Receptor Alpha Signaling in Triple-Negative Breast Cancer: Reactivation of Silenced ER-α and Signaling through ER-α36. Mol Cancer Res 2023; 21:1123-1138. [PMID: 37462782 DOI: 10.1158/1541-7786.mcr-23-0321] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/21/2023] [Accepted: 07/14/2023] [Indexed: 11/02/2023]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive tumor that accounts for approximately 15% of total breast cancer cases. It is characterized by poor prognosis and high rate of recurrence compared to other types of breast cancer. TNBC has a limited range of treatment options that include chemotherapy, surgery, and radiation due to the absence of estrogen receptor alpha (ER-α) rendering hormonal therapy ineffective. However, possible targets for improving the clinical outcomes in TNBC exist, such as targeting estrogen signaling through membranous ER-α36 and reactivating silenced ER-α. It has been shown that epigenetic drugs such as DNA methyltransferase and histone deacetylase inhibitors can restore the expression of ER-α. This reactivation of ER-α, presents a potential strategy to re-sensitize TNBC to hormonal therapy. Also, this review provides up-to-date information related to the direct involvement of miRNA in regulating the translation of ER-α mRNA. Specific epi-miRNAs can regulate ER-α expression indirectly by post-transcriptional targeting of mRNAs of enzymes that are involved in DNA methylation and histone deacetylation. Furthermore, ER-α36, an alternative splice variant of ER-α66, is highly expressed in ER-negative breast tumors and activates MAPK/ERK pathway, promoting cell proliferation, escaping apoptosis, and enhancing metastasis. In the future, these recent advances may be helpful for researchers working in the field to obtain novel treatment options for TNBC, utilizing epigenetic drugs and epi-miRNAs that regulate ER-α expression. Also, there is some evidence to suggest that drugs that decrease the expression of ER-α36 may be effective in treating TNBC.
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Affiliation(s)
- Aya Y Al-Kabariti
- Department of Biopharmaceutics and Clinical Pharmacy, Faculty of Pharmacy, Al-Ahliyya Amman University, Amman, Jordan
- Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
| | - Manal A Abbas
- Pharmacological and Diagnostic Research Centre, Al-Ahliyya Amman University, Amman, Jordan
- Department of Medical Laboratory Sciences, Faculty of Allied Medical Sciences, Al-Ahliyya Amman University, Amman, Jordan
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11
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Serioli S, Agostini L, Pietrantoni A, Valeri F, Costanza F, Chiloiro S, Buffoli B, Piazza A, Poliani PL, Peris-Celda M, Iavarone F, Gaudino S, Gessi M, Schinzari G, Mattogno PP, Giampietro A, De Marinis L, Pontecorvi A, Fontanella MM, Lauretti L, Rindi G, Olivi A, Bianchi A, Doglietto F. Aggressive PitNETs and Potential Target Therapies: A Systematic Review of Molecular and Genetic Pathways. Int J Mol Sci 2023; 24:15719. [PMID: 37958702 PMCID: PMC10650665 DOI: 10.3390/ijms242115719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/22/2023] [Accepted: 10/24/2023] [Indexed: 11/15/2023] Open
Abstract
Recently, advances in molecular biology and bioinformatics have allowed a more thorough understanding of tumorigenesis in aggressive PitNETs (pituitary neuroendocrine tumors) through the identification of specific essential genes, crucial molecular pathways, regulators, and effects of the tumoral microenvironment. Target therapies have been developed to cure oncology patients refractory to traditional treatments, introducing the concept of precision medicine. Preliminary data on PitNETs are derived from preclinical studies conducted on cell cultures, animal models, and a few case reports or small case series. This study comprehensively reviews the principal pathways involved in aggressive PitNETs, describing the potential target therapies. A search was conducted on Pubmed, Scopus, and Web of Science for English papers published between 1 January 2004, and 15 June 2023. 254 were selected, and the topics related to aggressive PitNETs were recorded and discussed in detail: epigenetic aspects, membrane proteins and receptors, metalloprotease, molecular pathways, PPRK, and the immune microenvironment. A comprehensive comprehension of the molecular mechanisms linked to PitNETs' aggressiveness and invasiveness is crucial. Despite promising preliminary findings, additional research and clinical trials are necessary to confirm the indications and effectiveness of target therapies for PitNETs.
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Affiliation(s)
- Simona Serioli
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy;
| | - Ludovico Agostini
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | | | - Federico Valeri
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Flavia Costanza
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Sabrina Chiloiro
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Barbara Buffoli
- Section of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25121 Brescia, Italy;
| | - Amedeo Piazza
- Department of Neuroscience, Neurosurgery Division, “Sapienza” University of Rome, 00185 Rome, Italy;
| | - Pietro Luigi Poliani
- Pathology Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele, 20132 Milan, Italy;
| | - Maria Peris-Celda
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN 55905, USA;
- Department of Otolaryngology/Head and Neck Surgery, Mayo Clinic, Rochester, MN 55905, USA
| | - Federica Iavarone
- Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, 20123 Rome, Italy;
- Fondazione Policlinico Universitario IRCCS “A. Gemelli”, 00168 Rome, Italy
| | - Simona Gaudino
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Radiological Sciences, Institute of Radiology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Marco Gessi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Neuropathology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Giovanni Schinzari
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Oncology, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Pier Paolo Mattogno
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Antonella Giampietro
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Laura De Marinis
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Alfredo Pontecorvi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Marco Maria Fontanella
- Division of Neurosurgery, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, 25123 Brescia, Italy;
| | - Liverana Lauretti
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Guido Rindi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Neuropathology Unit, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy
| | - Alessandro Olivi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
| | - Antonio Bianchi
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Pituitary Unit, Division of Endocrinology and Metabolism, Fondazione Policlinico Universitario A. Gemelli, IRCCS, 00168 Rome, Italy;
| | - Francesco Doglietto
- Facoltà di Medicina e Chirurgia, Università Cattolica del Sacro Cuore, 20123 Rome, Italy; (L.A.); (F.V.); (F.C.); (S.G.); (M.G.); (G.S.); (L.D.M.); (A.P.); (L.L.); (G.R.); (A.O.); (A.B.); (F.D.)
- Department of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, 00168 Rome, Italy;
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12
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Shivnani P, Shekhawat S, Prajapati A. Cancer Cachexia and breast cancer stem cell signalling - A crosstalk of signalling molecules. Cell Signal 2023; 110:110847. [PMID: 37557973 DOI: 10.1016/j.cellsig.2023.110847] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 08/05/2023] [Indexed: 08/11/2023]
Abstract
Cancer Cachexia is a condition characterized by the involuntary loss of lean body mass, a negative protein and energy balance, and systemic inflammation. This syndrome profoundly impacts the patient's quality of life and is linked to poor chemotherapy response and reduced survival. Despite multiple mechanisms being implicated in its development, and various cytokines believed to contribute to the persistent catabolic state, cachexia is still not fully recognized and is often left untreated. Cachexia is caused by altered metabolic adaptation and lack of anticactic therapy due to systemic cytokines promoting and fuelling cancer growth. The exact molecular mechanisms and clinical endpoints remain poorly defined. It has an occurrence rate of 30%-80%, accounting for 20% of total cancer mortality. Tumor cells remodel the microenvironment suitable for their proliferation, wherein they communicate with fibroblast cells to modulate their expression and induce tumor progressive cytokines. Several studies have reported its strong correlation with systemic cytokines that initiate and aggravate the condition. Plenty of studies show the prominent role of cancer-induced cachexia in pancreatic cancer, colon cancer, and lung cancer. However, limited data are available for breast cancer-induced cachexia, highlighting the need for studying it. Breast cancer stem cells (BCSCs) are a prominently explored area in breast cancer research. They are characterized by CD44+/CD24-/ALDH+ expression and are a focus of cancer research. They are a source of renewal and differentiation within the tumor environment and are responsible for progression, and chemotherapeutic resistance. The tumor microenvironment and its cytokines are responsible for maintaining and inducing their differentiation. Cytokines significantly impact BCSC development and self-renewal, stimulating or inhibiting proliferation depending on cytokine and environment. Pro-inflammatory mediators like IL-6, TNF-α, and IL-8 increase proliferation, promoting tumor growth. Experimental models and clinical studies have shown a direct relationship between cytokines and BCSC proliferation. Several of them seem to be interconnected as they initiate signalling down different pathways but converge at BCSC increase and tumor proliferation. This review highlights the common pathways between cachexia and BCSC signalling, to identify potential therapeutic targets that can aid both conditions.
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Affiliation(s)
- Priyanka Shivnani
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India
| | - Saroj Shekhawat
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India
| | - Akhilesh Prajapati
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India.
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Miziak P, Baran M, Błaszczak E, Przybyszewska-Podstawka A, Kałafut J, Smok-Kalwat J, Dmoszyńska-Graniczka M, Kiełbus M, Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers (Basel) 2023; 15:4689. [PMID: 37835383 PMCID: PMC10572081 DOI: 10.3390/cancers15194689] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens' synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies' development.
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Affiliation(s)
- Paulina Miziak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Marzena Baran
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Ewa Błaszczak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Jolanta Smok-Kalwat
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland;
| | - Magdalena Dmoszyńska-Graniczka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Michał Kiełbus
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
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Belluti S, Imbriano C, Casarini L. Nuclear Estrogen Receptors in Prostate Cancer: From Genes to Function. Cancers (Basel) 2023; 15:4653. [PMID: 37760622 PMCID: PMC10526871 DOI: 10.3390/cancers15184653] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 09/01/2023] [Accepted: 09/18/2023] [Indexed: 09/29/2023] Open
Abstract
Estrogens are almost ubiquitous steroid hormones that are essential for development, metabolism, and reproduction. They exert both genomic and non-genomic action through two nuclear receptors (ERα and ERβ), which are transcription factors with disregulated functions and/or expression in pathological processes. In the 1990s, the discovery of an additional membrane estrogen G-protein-coupled receptor augmented the complexity of this picture. Increasing evidence elucidating the specific molecular mechanisms of action and opposing effects of ERα and Erβ was reported in the context of prostate cancer treatment, where these issues are increasingly investigated. Although new approaches improved the efficacy of clinical therapies thanks to the development of new molecules targeting specifically estrogen receptors and used in combination with immunotherapy, more efforts are needed to overcome the main drawbacks, and resistance events will be a challenge in the coming years. This review summarizes the state-of-the-art on ERα and ERβ mechanisms of action in prostate cancer and promising future therapies.
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Affiliation(s)
- Silvia Belluti
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (C.I.)
| | - Carol Imbriano
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; (S.B.); (C.I.)
| | - Livio Casarini
- Unit of Endocrinology, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Ospedale di Baggiovara, 41126 Modena, Italy
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15
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Zhu Z, Jiang L, Ding X. Advancing Breast Cancer Heterogeneity Analysis: Insights from Genomics, Transcriptomics and Proteomics at Bulk and Single-Cell Levels. Cancers (Basel) 2023; 15:4164. [PMID: 37627192 PMCID: PMC10452610 DOI: 10.3390/cancers15164164] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 07/23/2023] [Accepted: 08/16/2023] [Indexed: 08/27/2023] Open
Abstract
Breast cancer continues to pose a significant healthcare challenge worldwide for its inherent molecular heterogeneity. This review offers an in-depth assessment of the molecular profiling undertaken to understand this heterogeneity, focusing on multi-omics strategies applied both in traditional bulk and single-cell levels. Genomic investigations have profoundly informed our comprehension of breast cancer, enabling its categorization into six intrinsic molecular subtypes. Beyond genomics, transcriptomics has rendered deeper insights into the gene expression landscape of breast cancer cells. It has also facilitated the formulation of more precise predictive and prognostic models, thereby enriching the field of personalized medicine in breast cancer. The comparison between traditional and single-cell transcriptomics has identified unique gene expression patterns and facilitated the understanding of cell-to-cell variability. Proteomics provides further insights into breast cancer subtypes by illuminating intricate protein expression patterns and their post-translational modifications. The adoption of single-cell proteomics has been instrumental in this regard, revealing the complex dynamics of protein regulation and interaction. Despite these advancements, this review underscores the need for a holistic integration of multiple 'omics' strategies to fully decipher breast cancer heterogeneity. Such integration not only ensures a comprehensive understanding of breast cancer's molecular complexities, but also promotes the development of personalized treatment strategies.
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Affiliation(s)
- Zijian Zhu
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
| | - Lai Jiang
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200025, China;
| | - Xianting Ding
- State Key Laboratory of Oncogenes and Related Genes, Institute for Personalized Medicine, Shanghai Jiao Tong University, Shanghai 200030, China;
- Department of Anesthesiology and Surgical Intensive Care Unit, Xinhua Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200025, China;
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Yin L, Chen GL, Xiang Z, Liu YL, Li XY, Bi JW, Wang Q. Current progress in chimeric antigen receptor-modified T cells for the treatment of metastatic breast cancer. Biomed Pharmacother 2023; 162:114648. [PMID: 37023621 DOI: 10.1016/j.biopha.2023.114648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/30/2023] [Accepted: 03/31/2023] [Indexed: 04/07/2023] Open
Abstract
Breast cancer is the leading cancer in women. Around 20-30% breast cancer patients undergo invasion or metastasis after radical surgical resection and eventually die. Number of breast cancer patients show poor sensitivity toward treatments despite the advances in chemotherapy, endocrine therapy, and molecular targeted treatments. Therapeutic resistance and tumor recurrence or metastasis develop with the ongoing treatments. Conducive treatment strategies are thus required. Chimeric antigen receptor (CAR)-modified T-cell therapy has progressed as a part of tumor immunotherapy. However, CAR-T treatment has not been effective in solid tumors because of tumor microenvironment complexity, inhibitory effects of extracellular matrix, and lacking ideal tumor antigens. Herein, the prospects of CAR-T cell therapy for metastatic breast cancer are discussed, and the targets for CAR-T therapy in breast cancer (HER-2, C-MET, MSLN, CEA, MUC1, ROR1, EGFR) at clinical level are reviewed. Moreover, solutions are proposed for the challenges of breast cancer CAR-T therapy regarding off-target effects, heterogeneous antigen expression by tumor cells and immunosuppressive tumor microenvironment. Ideas for improving the therapeutics of CAR-T cell therapy in metastatic breast cancer are suggested.
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Affiliation(s)
- Li Yin
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Shandong University of Traditional Chinese Medicine, 250355 Jinan, China
| | - Gui-Lai Chen
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Zhuo Xiang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Yu-Lin Liu
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China
| | - Xing-Yu Li
- Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China
| | - Jing-Wang Bi
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China.
| | - Qiang Wang
- Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Cheeloo College of Medicine, Shandong University, 250023 Jinan, China; Oncology Department, Shandong Second Provincial General Hospital, 250023 Jinan, China; Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, 266003 Qingdao, China.
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Li H, Ge N, Guan X, Han C, Li Y, Shen L, Chen M, Zhang B, Qu C, Zou W. The location of estrogen receptor variant ER-α36 is associated with the invasion of glioblastoma. Steroids 2023; 194:109224. [PMID: 36924815 DOI: 10.1016/j.steroids.2023.109224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 03/12/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023]
Abstract
Glioblastoma (GBM) is the most common central nervous system tumor and is associated with poor outcomes. There have been no significant improvements in GBM mortality in recent decades. ER-α36 is a variant of ER-α66 that may be involved in carcinoma growth and proliferation via genomic and nongenomic mechanisms. This variant might play an essential role in tamoxifen resistance of several tumors. Previously, our laboratory found that ER-α36 is expressed in GBM and participates in proliferation; nevertheless, the role of ER-α36 in GBM invasion remains unknown. This study aimed to determine the effects of the ER-α36 modulator SNG162 on GBM growth and invasion. U251 cells, U87cells, and U87-36KD cells with knockdown of ER-α36 expression were cultured under the two-dimensional and the three-dimensional (3D) environments. GBM cells growth was examined by cell counting, flow cytometry, western blot, and MTT assays. Invasiveness was measured using confocal microscopy in the 3D environment. Growth of U87 cells with downregulated EGFR and ER-α36 expression was significantly reduced after treatment with 1 µM, 3 µM, and 5 µM of SNG162; growth inhibition in U251 cells was more potent than in U87 cells, although the expression level of ER-α36 in U251 cells was lower than in U87 cells. We found that 1 μM SNG162 suppressed E2-induced MAPK/ERK pathway activation in U87 cells. We also showed that SNG162 inhibited U87 cells invasion; however, it did not significantly affect U251 and U87-36KD cells invasion using the 3D culture method. Finally, we determined that ER-α36 was expressed in the nucleus of invading GBM cells, and SNG162 significantly inhibited the expression of ER-α36 in these cells. SNG162 inhibited the expression of EGFR on cell membranes of non-invasive GBM cells. These results suggest that SNG162 could be a therapeutic agent for GBM by targeting ER-α36.
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Affiliation(s)
- Hongyan Li
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, China
| | - Nan Ge
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xin Guan
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, China; Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chao Han
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ying Li
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Liming Shen
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Mengmeng Chen
- Qingdao Re-store Life Science Co., Ltd., Qingdao, Shandong, China
| | - Bingqiang Zhang
- Qingdao Re-store Life Science Co., Ltd., Qingdao, Shandong, China
| | - Chao Qu
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, China; Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.
| | - Wei Zou
- Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Science, Liaoning Normal University, Dalian, China; Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China; Qingdao Re-store Life Science Co., Ltd., Qingdao, Shandong, China.
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18
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Estrogen Receptor Alpha Splice Variants, Post-Translational Modifications, and Their Physiological Functions. Cells 2023; 12:cells12060895. [PMID: 36980236 PMCID: PMC10047206 DOI: 10.3390/cells12060895] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/08/2023] [Accepted: 03/11/2023] [Indexed: 03/17/2023] Open
Abstract
The importance of estrogenic signaling for a broad spectrum of biological processes, including reproduction, cancer development, energy metabolism, memory and learning, and so on, has been well documented. Among reported estrogen receptors, estrogen receptor alpha (ERα) has been known to be a major mediator of cellular estrogenic signaling. Accumulating evidence has shown that the regulations of ERα gene transcription, splicing, and expression across the tissues are highly complex. The ERα promoter region is composed of multiple leader exons and 5′-untranslated region (5′-UTR) exons. Differential splicing results in multiple ERα proteins with different molecular weights and functional domains. Furthermore, various post-translational modifications (PTMs) further impact ERα cellular localization, ligand affinity, and therefore functionality. These splicing isoforms and PTMs are differentially expressed in a tissue-specific manner, mediate certain aspects of ERα signaling, and may work even antagonistically against the full-length ERα. The fundamental understanding of the ERα splicing isoforms in normal physiology is limited and association studies of the splicing isoforms and the PTMs are scarce. This review aims to summarize the functional diversity of these ERα variants and the PTMs in normal physiological processes, particularly as studied in transgenic mouse models.
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Davis D, Vajaria R, Delivopoulos E, Vasudevan N. Localisation of oestrogen receptors in stem cells and in stem cell-derived neurons of the mouse. J Neuroendocrinol 2023; 35:e13220. [PMID: 36510342 PMCID: PMC10909416 DOI: 10.1111/jne.13220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 10/24/2022] [Accepted: 11/09/2022] [Indexed: 11/25/2022]
Abstract
Oestrogen receptors (ER) transduce the effects of the endogenous ligand, 17β-estradiol in cells to regulate a number of important processes such as reproduction, neuroprotection, learning and memory and anxiety. The ERα or ERβ are classical intracellular nuclear hormone receptors while some of their variants or novel proteins such as the G-protein coupled receptor (GPCR), GPER1/GPR30 are reported to localise in intracellular as well as plasma membrane locations. Although the brain is an important target for oestrogen with oestrogen receptors expressed differentially in various nuclei, subcellular organisation and crosstalk between these receptors is under-explored. Using an adapted protocol that is rapid, we first generated neurons from mouse embryonic stem cells. Our immunocytochemistry approach shows that the full length ERα (ERα-66) and for the first time, that an ERα variant, ERα-36, as well as GPER1 is present in embryonic stem cells. In addition, these receptors typically decrease their nuclear localisation as neuronal maturation proceeds. Finally, although these ERs are present in many subcellular compartments such as the nucleus and plasma membrane, we show that they are specifically not colocalised with each other, suggesting that they initiate distinct signalling pathways.
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Affiliation(s)
- DeAsia Davis
- School of Biological Sciences, University of Reading, Reading, UK
| | - Ruby Vajaria
- School of Biological Sciences, University of Reading, Reading, UK
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20
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Park M, Lee SH, Bui QT, Kim YM, Kang KW. The essential role of YAP in ERα36-mediated proliferation and the epithelial-mesenchymal transition in MCF-7 breast cancer cells. Front Pharmacol 2022; 13:1057276. [PMID: 36534032 PMCID: PMC9755719 DOI: 10.3389/fphar.2022.1057276] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/21/2022] [Indexed: 08/15/2023] Open
Abstract
Purpose: Most breast cancers are hormone-receptor-positive, and thus the first-line therapy for them is an anti-estrogen medication such as tamoxifen. If metastasis occurs or resistance to tamoxifen develops, the 5-year survival rates for breast cancer patients significantly decrease. Hence, a better understanding of the molecular mechanisms that contribute to breast cancer aggressiveness is of great importance. ERα36 is an estrogen receptor variant that is known to be upregulated in breast cancer patients receiving tamoxifen treatment or in triple-negative breast cancer cells. However, the specific molecular mechanism underlying ERα36-induced tamoxifen-resistance is not yet fully understood. Methods: ERα36-overexpressing MCF-7 cells were constructed by either plasmid transfection using ERα36 vector or retroviral infection using ERα36-V5-His vector. Target-gene expression was assessed by Western blot analysis and real-time PCR, and YAP activation was evaluated by luciferase assays and immunofluorescence. Cell proliferation and formation of three-dimensional spheroids were evaluated using the IncuCyte S3 Live Cell Analysis System. Results: We found that the expression patterns of Hippo signaling-related genes were significantly changed in ERα36-overexpressing MCF-7 cells compared to MCF-7 cells, which were also similarly observed in tamoxifen-resistant MCF-7 cells. Specifically, the protein expression level and activity of YAP, the core downstream protein of the Hippo pathway, were significantly increased in ERα36-overexpressing MCF-7 cells compared with MCF-7 cells. The aggressive phenotypes acquired by ERα36 overexpression in MCF-7 cells were destroyed by YAP knockout. On this basis, we propose that ERα36 regulates YAP activity by a new mechanism involving Src kinase. Conclusion: Our results suggest that YAP targeting may be a new therapeutic approach to the treatment of advanced breast cancers overexpressing ERα36.
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Affiliation(s)
- Miso Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Seung Hyun Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Quyen Thu Bui
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
| | - Young-Mi Kim
- Department of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, South Korea
| | - Keon Wook Kang
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea
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21
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Pan X, Song Z, Cui Y, Qi M, Wu G, Wang M. Enhancement of Sensitivity to Tamoxifen by Berberine in Breast Cancer Cells by Inhibiting ER-α36 Expression. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2022; 21:e126919. [PMID: 36060924 PMCID: PMC9420211 DOI: 10.5812/ijpr-126919] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 09/30/2020] [Accepted: 11/08/2020] [Indexed: 05/31/2023]
Abstract
Berberine, an isoquinoline alkaloid purified from Chinese herbs, was verified to have antitumor effects. It has also been reported that berberine can enhance the anticancer effect of tamoxifen (TAM) in estrogen receptor (ER)-positive breast cancer cells; however, the involved underlying mechanism is still unclear. In the present study, the role of one variant of ER-α, ER-α36, in the TAM sensitizing effect of berberine was explored in TAM-resistant breast cancer cells. This study demonstrated that berberine potently sensitized TAM-resistant breast cancer cells, including TAM-resistant MCF7 and BT-474 cells, to TAM treatment. Additionally, this study showed that berberine could simultaneously suppress ER-α36 expression in TAM-resistant cells. However, when ER-α36 was knocked down in TAM-resistant cells, there was no significant TAM-sensitizing effect by berberine. Therefore, this study indicated that ER-α36 is involved in berberine's TAM-sensitizing effect on ER-positive breast cancer cells, which provided supporting data for the application of berberine in cancer therapy as an adjuvant agent for TAM treatment.
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Affiliation(s)
- Xiaohua Pan
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Zhen Song
- Department of Obstetrics and Gynecology, Shandong University Qilu Hospital, Jinan, 250012, Shandong, China
| | - Yue Cui
- University of Jinan, Jinan, 250022, Shandong, China
| | - Ming Qi
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Guojun Wu
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
| | - Molin Wang
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University, Jinan, 250012, Shandong, China
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22
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Khan MZI, Uzair M, Nazli A, Chen JZ. An overview on Estrogen receptors signaling and its ligands in breast cancer. Eur J Med Chem 2022; 241:114658. [PMID: 35964426 DOI: 10.1016/j.ejmech.2022.114658] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 07/31/2022] [Accepted: 08/01/2022] [Indexed: 02/07/2023]
Abstract
Estrogen governs the regulations of various pathological and physiological actions throughout the body in both males and females. Generally, 17β-estradiol an endogenous estrogen is responsible for different health problems in pre and postmenopausal women. The major activities of endogenous estrogen are executed by nuclear estrogen receptors (ERs) ERα and ERβ while non-genomic cytoplasmic pathways also govern cell growth and apoptosis. Estrogen accomplished a fundamental role in the formation and progression of breast cancer. In this review, we have hyphenated different studies regarding ERs and a thorough and detailed study of estrogen receptors is presented. This review highlights different aspects of estrogens ranging from receptor types, their isoforms, structures, signaling pathways of ERα, ERβ and GPER along with their crystal structures, pathological roles of ER, ER ligands, and therapeutic strategies to overcome the resistance.
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Affiliation(s)
| | - Muhammad Uzair
- School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, 450001, China
| | - Adila Nazli
- Department of Pharmacy, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan
| | - Jian-Zhong Chen
- College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
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23
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Chemopreventive and therapeutic properties of anthocyanins in breast cancer: A comprehensive review. Nutr Res 2022; 107:48-64. [PMID: 36179643 DOI: 10.1016/j.nutres.2022.08.005] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 08/17/2022] [Accepted: 08/25/2022] [Indexed: 12/27/2022]
Abstract
Anthocyanins have received the attention of the scientific community because of their antioxidant, antimetastatic, and cancer-inhibitory properties. The aim of this review is to comprehensively summarize the possible mechanisms by which anthocyanins exhibit anticarcinogenic properties in breast cancer (BC) cell lines and animal models. Anthocyanins inhibit proinflammatory, signal transducer and activator of transcription 3, and nuclear factor kappa-light-chain-enhancer of activated B cell pathways and increase the activities of detoxification enzymes. In addition, downregulation of metalloproteinases by anthocyanins inhibits tumor invasion and metastatic processes in experimental systems. Anthocyanins mediate anticancer and angiogenic effects by modifying multiple receptor families. Furthermore, inhibition of cell-cycle upstream polo-like kinase signaling, the chromosomal replication checkpoint, and ataxia telangiectasia mutated signaling may contribute to the anticarcinogenic effects of anthocyanins. Finally, anthocyanins induce mitochondrial-mediated apoptosis and downregulate the phosphatidylinositol-3-kinase/AKT/mTOR pathway. In conclusion, anthocyanins have been shown to exert potential antitumor effects against breast carcinogenesis in vitro and in vivo, providing insights into the use of anthocyanins as a natural chemopreventive intervention in BC.
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24
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Saito K, Dickey JE, Rodeghiero SR, Toth BA, Kelly MJ, Deng Y, Singh U, Deng G, Jiang J, Cui H. Hypomorphism of a Novel Long ERα Isoform Causes Severe Reproductive Dysfunctions in Female Mice. Endocrinology 2022; 163:6742225. [PMID: 36181426 DOI: 10.1210/endocr/bqac160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Indexed: 11/19/2022]
Abstract
Estrogen receptor alpha (ERα)-mediated estrogen signaling plays a pivotal role in both reproductive and nonreproductive functions. Transcriptional regulation of the ERα gene is highly complex, with multiple transcript variants being differentially produced across the tissues. However, tissue-specific variation and physiological specificity of the ERα variants are not yet fully understood. In an attempt to generate a Cre-dependently restorable ERα-null mouse for functional genetic studies, we unexpectedly produced ERα hypomorphic mice with biased downregulation of a previously unappreciated long ERα isoform that is enriched in the female reproductive organs (uterus and ovaries) and the pituitary but minimally expressed in the brain. Female homozygous mutant mice were capable of pregnancy but displayed irregular estrus cycle and rarely kept newborn pups alive. No significant morphological and pathological changes in reproductive system or disruption of body weight homeostasis were seen in female homozygous mutant mice. Collectively, our results define a tissue-specific enriched long ERα isoform and its preferential role in female reproductive function rather than body weight homeostasis.
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Affiliation(s)
- Kenji Saito
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Jacob E Dickey
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Samuel R Rodeghiero
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Brandon A Toth
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Matthew J Kelly
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Yue Deng
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Uday Singh
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Guorui Deng
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Jingwei Jiang
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
| | - Huxing Cui
- Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
- Iowa Neuroscience Institute, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
- F.O.E. Diabetes Research Center, University of Iowa Carver College of Medicine, Iowa City, IA 52241, USA
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25
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Modulation of SOCS3 Levels via STAT3 and Estrogen-ERαp66 Signaling during Hepatitis E Virus Replication in Hepatocellular Carcinoma Cells. J Virol 2022; 96:e0100822. [PMID: 36102649 PMCID: PMC9555149 DOI: 10.1128/jvi.01008-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Hepatitis E virus (HEV) infection usually results in a self-limiting acute disease; however, in infected pregnant women, it is associated with increased mortality and fulminant hepatic failure. Estrogen is known to be elevated during pregnancy, and estrogen signaling via classical estrogen receptor-ERα is known to regulate hepatocyte function and host innate immune response, including the STAT3 pathway. In this study, we investigated whether the estrogen classical signaling pathway via ERαp66 has any effect on STAT3 activation during HEV replication and HEV-induced IFN response. We first demonstrated that Huh7-S10-3 liver cells expressed the nonfunctional estrogen receptor ERαp36 isoform and lack the functional ERαp66 isoform. We further showed persistent phosphorylated-STAT3 levels in genotype 3 human HEV (Kernow P6 strain) RNA-transfected cells at later time points. In Huh7-S10-3 cells, estrogen at first-to-third trimester concentration (7.3 to 73 nM) did not significantly affect HEV replication; however, blocking of STAT3 activation led to a decrease in the HEV ORF2 protein level. Our mechanistic study revealed that STAT3 differentially regulates SOCS3 and type-III interferon (IFN) levels during HEV replication and the presence of estrogen-ERαp66 signaling stabilizes SOCS3 levels in vitro. We also demonstrate that HEV infection in pregnant and nonpregnant rabbits led to a significant increase in IFN response as measured by increased levels of IFN-stimulated-gene-15 (ISG15) mRNA levels irrespective of pregnancy status. Collectively, the results indicate that estrogen signaling and STAT3 regulate SOCS3 and IFN responses in vitro during HEV replication. The results have important implications for understanding HEV replication and HEV-induced innate immune response in pregnant women. IMPORTANCE Hepatitis E is usually a self-resolving acute disease; however, in pregnant women, HEV infection is associated with high mortality and fulminant hepatic failure. During pregnancy, estrogen levels are elevated, and in the liver, the estrogen receptor ERα is predominant and estrogen signaling is known to regulate hepatocyte metabolism and leptin-induced STAT3 levels. Viruses can module host innate immune response via STAT3. Therefore, in this study, we investigated whether STAT3 and estrogen-classical signaling via the ERαp66 pathway modulate HEV replication and HEV-induced innate immune response. We demonstrated that estrogen signaling did not affect HEV replication in human liver cells, but blocking of STAT3 activation reduced HEV capsid protein levels in human liver cells. We also showed that inhibition of STAT3 activation reduced SOCS3 levels, while the presence of the estrogen-ERαp66 signaling pathway stabilized SOCS3 levels. The results from this study will aid our understanding of the mechanism of HEV pathogenesis and immune response during pregnancy.
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26
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Qu C, Wang C, Li H, Li Y, Han C, Tao X, Guan X, Zhang Y, Chen M, Liu J, Zou W. Estrogen receptor variant ER-α36 facilitates estrogen signaling via EGFR in glioblastoma. Cell Biol Int 2022; 46:1759-1774. [PMID: 35930599 DOI: 10.1002/cbin.11877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 03/15/2022] [Accepted: 03/28/2022] [Indexed: 11/08/2022]
Abstract
Glioblastoma (GBM) is a deadly and common primary brain tumor. Poor prognosis is linked to high proliferation and cell heterogeneity. Sex differences may play a role in patient outcome. Previous studies showed that ER-α36, a variant of the estrogen receptor (ER), mediated non-genomic estrogen signaling and is highly expressed in many ER-negative malignant tumors. ER-α36 also associates with epidermal growth factor receptor (EGFR). The primary purpose of this study is to investigate the cross talk between ER-α36 and EGFR in estrogen-mediated GBM cell proliferation. Here, we showed that ER-α36 was highly expressed and confirmed that ER-α36 co-labels with EGFR in human GBM samples using immunohistochemical techniques. We also investigated the mechanisms of estrogen-induced proliferation in ER-α-negative cell lines. We found that GBM cells showed varying responsive to mitogenic estrogen signaling which correlated with ER-α36 expression, and knockdown of ER-α36 diminished the response. Exposure to estrogen also caused upregulation of cyclin protein expression in vitro. We also found that low concentration of estrogen promoted SRC-Y-416 and inhibited SRC-Y-527 phosphorylation, corresponding with activated SRC signaling. Inhibiting SRC or EGFR abolished estrogen-induced mitogenic signaling, including cyclin expression and MAPK phosphorylation. Cumulatively, our results demonstrate that ER-α36 promotes non-genomic estrogen signaling via the EGFR/SRC/MAPK pathway in GBM. This may be important for the treatment of ER-α-negative GBMs that retain high level of ER-α36, since estrogen may be a viable therapeutic target for these patients.
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Affiliation(s)
- Chao Qu
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China.,Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Cui Wang
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China.,Neurology Ward Three, Dalian Municipal Central Hospital, Dalian, Liaoning, China
| | - Hongyan Li
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China
| | - Ying Li
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Chao Han
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Xiaofeng Tao
- Neurology Ward Three, Dalian Municipal Central Hospital, Dalian, Liaoning, China
| | - Xin Guan
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China.,Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Yejun Zhang
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China
| | - Meng Chen
- Qingdao Re-store Life Science Co., Ltd., Qingdao, Shandong, China
| | - Jing Liu
- Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Wei Zou
- College of Life Science, Liaoning Normal University, Dalian, Liaoning, China.,Stem Cell Clinical Research Center, National Joint Engineering Laboratory, Regenerative Medicine Center, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China.,Qingdao Re-store Life Science Co., Ltd., Qingdao, Shandong, China
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27
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Li K, Zong D, Sun J, Chen D, Ma M, Jia L. Rewiring of the Endocrine Network in Triple-Negative Breast Cancer. Front Oncol 2022; 12:830894. [PMID: 35847875 PMCID: PMC9280148 DOI: 10.3389/fonc.2022.830894] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 01/31/2022] [Indexed: 12/19/2022] Open
Abstract
The immunohistochemical definition of estrogen/progesterone receptors dictates endocrine feasibility in the treatment course of breast cancer. Characterized by the deficiency of estrogen receptor α, ERα-negative breast cancers are dissociated from any endocrine regimens in the routine clinical setting, triple-negative breast cancer in particular. However, the stereotype was challenged by triple-negative breast cancers’ retained sensitivity and vulnerability to endocrine agents. The interplay of hormone action and the carcinogenic signaling program previously underscored was gradually recognized along with the increasing investigation. In parallel, the overlooked endocrine-responsiveness in ERα-negative breast cancers attracted attention and supplied fresh insight into the therapeutic strategy in an ERα-independent manner. This review elaborates on the genomic and non-genomic steroid hormone actions and endocrine-related signals in triple-negative breast cancers attached to the hormone insensitivity label. We also shed light on the non-canonical mechanism detected in common hormone agents to showcase their pleiotropic effects.
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Affiliation(s)
- Kaixuan Li
- Department of Integrated Traditional Chinese and Western Medicine Oncology, China-Japan Friendship Hospital, Beijing, China
- Beijing University of Chinese medicine, Beijing, China
| | | | - Jianrong Sun
- School of Clinical Medicine. Beijing University of Chinese Medicine, Beijing, China
| | - Danxiang Chen
- Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Minkai Ma
- Department of Integrated Traditional Chinese and Western Medicine Oncology, The Fourth Central Hospital, Baoding, China
| | - Liqun Jia
- Department of Integrated Traditional Chinese and Western Medicine Oncology, China-Japan Friendship Hospital, Beijing, China
- *Correspondence: Liqun Jia,
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28
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Wang R, Chen J, Yu H, Wei Z, Ma M, Ye X, Wu W, Chen H, Fu Z. Downregulation of estrogen receptor-α36 expression attenuates metastasis of hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:1113-1123. [PMID: 35044086 DOI: 10.1002/tox.23469] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 06/14/2023]
Abstract
This study aimed to examine the role of estrogen receptor (ER)-α36 in the metastasis of hepatocellular carcinoma (HCC) and in the epithelial-mesenchymal transition (EMT). HCC HepG2 and Huh7 cells with the knocked-down level of ER-α36 expression were established. Cell growth and migration of the HepG2 and Huh7 cell variants were studied using MTS, transwell, and wound-healing assays, and the metastatic abilities of HepG2 cell variants were examined using a tail-vein injection model in nude mice. Levels of EMT markers, Src phosphorylation in HepG2 and Huh7 cell variants, and tumors formed by HepG2 cell variants in the nude mice were examined using Western blot and immunohistochemistry. We found that the growth and metastatic abilities of HepG2 and Huh7 cells with the knocked-down level of ER-α36 expression (HepG2/Si36 and Huh7/Si36) were significantly reduced, with increased levels of cytokeratin and E-Cadherin expression, and decreased levels of Vimentin, Snail, Slug and the Src phosphorylation, compared to the HCC cells transfected with an empty vector (HepG2/Vector and Huh7/Vector). We also found ER-α36 knockdown suppressed the lung metastasis of HepG2 cells with the involvement of EMT and the Src pathway in vivo. The Src inhibitor PP2 suppressed the growth and migration of HepG2/Vector and Huh7/Vector cells with decreased Vimentin, Snail, and Slug and increased cytokeratin and E-Cadherin expressions, but failed to induce the migration and the EMT markers in HepG2/Si36 and Huh7/Si36 cells. ER-α36 is involved in the metastasis of HCC cells through the regulation of EMT and the Src signaling pathway.
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Affiliation(s)
- Ruobing Wang
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Jiaming Chen
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Haiyan Yu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Zhixuan Wei
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Min Ma
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
- Intensive Care Unit, Huazhong University of Science and Technology Union Jiangbei Hospital, Wuhan, China
| | - Xueyan Ye
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Weiqi Wu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Hongfei Chen
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
| | - Zhengqi Fu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, China
- Cancer Institute, Jianghan University, Wuhan, China
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29
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Yonehara K, Zhou Y, Takahashi JI, Yokoyama S, Tomihara K, Noguchi M, Sakurai H. RSK-Mediated Non-canonical Activation of EphA2 by Tamoxifen. Biol Pharm Bull 2022; 45:162-168. [PMID: 35110502 DOI: 10.1248/bpb.b21-00567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.
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Affiliation(s)
- Keisuke Yonehara
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama.,Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Yue Zhou
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Jun-Ichiro Takahashi
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Satoru Yokoyama
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
| | - Kei Tomihara
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Makoto Noguchi
- Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama
| | - Hiroaki Sakurai
- Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama
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30
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Elliot SJ, Catanuto P, Pereira-Simon S, Xia X, Pastar I, Thaller S, Head CR, Stojadinovic O, Tomic-Canic M, Glassberg MK. Catalase, a therapeutic target in the reversal of estrogen-mediated aging. Mol Ther 2022; 30:947-962. [PMID: 34174444 PMCID: PMC8821897 DOI: 10.1016/j.ymthe.2021.06.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/30/2021] [Accepted: 06/09/2021] [Indexed: 02/04/2023] Open
Abstract
Despite increasing interest in the reversal of age-related processes, there is a paucity of data regarding the effects of post-menopausal-associated estrogen loss on cellular function. We studied human adipose-derived mesenchymal stem cells (hASCs) isolated from women younger than 45 years old (pre-menopause, pre-hASC) or older than 55 years old (post-menopause, post-hASC). In this study, we provide proof of concept that the age-related ineffective functionality of ASCs can be reversed to improve their ability in promoting tissue repair. We found reduced estrogen receptor expression, decreased estrogen receptor activation, and reduced sensitivity to 17β-estradiol in post-hASCs. This correlated with decreased antioxidants (catalase and superoxide dismutase [SOD] expression) and increased oxidative stress compared with pre-hASCs. Increasing catalase expression in post-hASCs restored estrogen receptor (ER) expression and their functional capacity to promote tissue repair as shown in human skin ex vivo wound healing and in vivo mouse model of lung injury. Our results suggest that the consequences of 17β-estradiol decline on the function of hASCs may be reversible by changing the oxidative stress/antioxidant composition.
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Affiliation(s)
- Sharon J. Elliot
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Corresponding author: Sharon J. Elliot, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
| | - Paola Catanuto
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Simone Pereira-Simon
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Seth Thaller
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Cheyanne R. Head
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Olivera Stojadinovic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marilyn K. Glassberg
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA,Corresponding author: Marilyn K. Glassberg, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
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Wu W, Chen H, Wang R, Chen J, Yu H, Wei Z, Liu X, Xue M, Chen Q, Zhou H, Fu Z. Estrogen receptor-α36 is involved in diallyl sulfide-induced inhibition of malignant growth of HepG2 and Huh7 hepatocellular carcinoma cells. ENVIRONMENTAL TOXICOLOGY 2022; 37:270-281. [PMID: 34724321 DOI: 10.1002/tox.23396] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 10/01/2021] [Accepted: 10/22/2021] [Indexed: 06/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant disease that currently lacks effective treatment. Epidemiological studies have suggested the preventive role of raw garlic intake in different tumors, such as HCC. Although diallyl sulfide (DAS), the main component of garlic extracts, has been reported to inhibit the growth of HCC cells, the underlying mechanism remains elusive. This study aimed to investigate the inhibitory effect of DAS on the growth of HepG2 and Huh7 hepatocellular carcinoma cells and its underlying mechanism. HepG2 and Huh7 cells were treated with DAS and nude mice were intrahepatically injected with human HCC HepG2 cells and maintained with or without DAS administration for 28 days. MTS and clonogenic assays revealed that DAS inhibited the growth and clonogenicity of HepG2 and Huh7 hepatocellular carcinoma cells. Furthermore, DAS inhibited the growth of xenograft tumors accompanied by a decreased rate of pathological karyomitosis as observed by H&E staining. The expression levels of estrogen receptor-α36 (ER-α36) and epidermal growth factor receptor (EGFR) in HepG2 and Huh7 cells and in xenograft tumors derived from HepG2 cells after DAS treatment were detected by immunohistochemistry and western blotting. We found that DAS disrupted the positive regulatory loop between ER-α36 and EGFR, and decreased the phosphorylation of AKT at Ser 473 both in vivo and in vitro. DAS also induced cell apoptosis, as evidenced by Hoechst and TUNEL staining. Western blotting revealed activation of caspase3, increased BAX and decreased Bcl-2 expression. However, the ER-α36 expression knockdown attenuated DAS-induced ERK and AKT phosphorylation in HCC cells. DAS was also able to inhibit ER-α36-mediated activation of the MAPK/ERK signaling induced by estrogen. Thus, our results indicate that ER-α36 signaling is involved in DAS-induced inhibition of HCC cell growth both in vitro and in vivo.
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Affiliation(s)
- Weiqi Wu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Hongfei Chen
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Ruobing Wang
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Jiaming Chen
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Haiyan Yu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Zhixuan Wei
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Xiaotian Liu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Mingru Xue
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Qiongxia Chen
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Hongyan Zhou
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
| | - Zhengqi Fu
- Department of Pathology and Pathophysiology, School of Medicine, Jianghan University, Wuhan, People's Republic of China
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Chimento A, De Luca A, Avena P, De Amicis F, Casaburi I, Sirianni R, Pezzi V. Estrogen Receptors-Mediated Apoptosis in Hormone-Dependent Cancers. Int J Mol Sci 2022; 23:1242. [PMID: 35163166 PMCID: PMC8835409 DOI: 10.3390/ijms23031242] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 01/14/2022] [Accepted: 01/17/2022] [Indexed: 02/04/2023] Open
Abstract
It is known that estrogen stimulates growth and inhibits apoptosis through estrogen receptor(ER)-mediated mechanisms in many cancer cell types. Interestingly, there is strong evidence that estrogens can also induce apoptosis, activating different ER isoforms in cancer cells. It has been observed that E2/ERα complex activates multiple pathways involved in both cell cycle progression and apoptotic cascade prevention, while E2/ERβ complex in many cases directs the cells to apoptosis. However, the exact mechanism of estrogen-induced tumor regression is not completely known. Nevertheless, ERs expression levels of specific splice variants and their cellular localization differentially affect outcome of estrogen-dependent tumors. The goal of this review is to provide a general overview of current knowledge on ERs-mediated apoptosis that occurs in main hormone dependent-cancers. Understanding the molecular mechanisms underlying the induction of ER-mediated cell death will be useful for the development of specific ligands capable of triggering apoptosis to counteract estrogen-dependent tumor growth.
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Affiliation(s)
- Adele Chimento
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Arianna De Luca
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Paola Avena
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Ivan Casaburi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Rosa Sirianni
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
| | - Vincenzo Pezzi
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via Pietro Bucci, Arcavacata di Rende, 87036 Cosenza, Italy
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Veiga DFT, Nesta A, Zhao Y, Mays AD, Huynh R, Rossi R, Wu TC, Palucka K, Anczukow O, Beck CR, Banchereau J. A comprehensive long-read isoform analysis platform and sequencing resource for breast cancer. SCIENCE ADVANCES 2022; 8:eabg6711. [PMID: 35044822 PMCID: PMC8769553 DOI: 10.1126/sciadv.abg6711] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Tumors display widespread transcriptome alterations, but the full repertoire of isoform-level alternative splicing in cancer is unknown. We developed a long-read (LR) RNA sequencing and analytical platform that identifies and annotates full-length isoforms and infers tumor-specific splicing events. Application of this platform to breast cancer samples identifies thousands of previously unannotated isoforms; ~30% affect protein coding exons and are predicted to alter protein localization and function. We performed extensive cross-validation with -omics datasets to support transcription and translation of novel isoforms. We identified 3059 breast tumor–specific splicing events, including 35 that are significantly associated with patient survival. Of these, 21 are absent from GENCODE and 10 are enriched in specific breast cancer subtypes. Together, our results demonstrate the complexity, cancer subtype specificity, and clinical relevance of previously unidentified isoforms and splicing events in breast cancer that are only annotatable by LR-seq and provide a rich resource of immuno-oncology therapeutic targets.
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Affiliation(s)
- Diogo F. T. Veiga
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Alex Nesta
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
- Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA
| | - Yuqi Zhao
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | | | - Richie Huynh
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Robert Rossi
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Te-Chia Wu
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Karolina Palucka
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
| | - Olga Anczukow
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
- Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA
- Corresponding author. (O.A.); (C.R.B.); (J.B.)
| | - Christine R. Beck
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
- Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA
- Institute for Systems Genomics, University of Connecticut Health Center, Farmington, CT 06030, USA
- Corresponding author. (O.A.); (C.R.B.); (J.B.)
| | - Jacques Banchereau
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
- Corresponding author. (O.A.); (C.R.B.); (J.B.)
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Decreased Expression of Estrogen Receptors Is Associated with Tumorigenesis in Papillary Thyroid Carcinoma. Int J Mol Sci 2022; 23:ijms23031015. [PMID: 35162942 PMCID: PMC8835567 DOI: 10.3390/ijms23031015] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 01/11/2022] [Accepted: 01/14/2022] [Indexed: 12/05/2022] Open
Abstract
Papillary thyroid carcinomas (PTC), which is derived from thyroid follicular cells, is the most commonly differentiated thyroid cancer with sex disparity. However, the role of estrogen receptors (ERs) in the pathogenesis of PTC remains unclear. The present study aimed to determine the association of ER mRNA expression levels with clinicopathologic features in PTC. To that aim, the mRNA levels of ESR1 (ERα66), ESR1 (ERα36), ESR2, and G-protein-coupled estrogen receptor 1 (GPER1) in snap-frozen tissue samples from PTCs and adjacent normal thyroid tissues were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the correlation between ER mRNA expression levels and clinicopathologic features was analyzed. The expression of ERα66, ERα36, ERβ, and GPER1 was lower in PTC specimens than in adjacent normal thyroid tissues. Moreover, low GPER1 expression was associated with extrathyroidal extension. There was no obvious difference in expression of ERs between PTC specimens from male and female patients. In conclusion, our findings highlight the importance of ERs in PTC tumorigenesis.
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Adlanmerini M, Fontaine C, Gourdy P, Arnal JF, Lenfant F. Segregation of nuclear and membrane-initiated actions of estrogen receptor using genetically modified animals and pharmacological tools. Mol Cell Endocrinol 2022; 539:111467. [PMID: 34626731 DOI: 10.1016/j.mce.2021.111467] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 09/06/2021] [Accepted: 09/28/2021] [Indexed: 11/23/2022]
Abstract
Estrogen receptor alpha (ERα) and beta (ERβ) are members of the nuclear receptor superfamily, playing widespread functions in reproductive and non-reproductive tissues. Beside the canonical function of ERs as nuclear receptors, in this review, we summarize our current understanding of extra-nuclear, membrane-initiated functions of ERs with a specific focus on ERα. Over the last decade, in vivo evidence has accumulated to demonstrate the physiological relevance of this ERα membrane-initiated-signaling from mouse models to selective pharmacological tools. Finally, we discuss the perspectives and future challenges opened by the integration of extra-nuclear ERα signaling in physiology and pathology of estrogens.
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Affiliation(s)
- Marine Adlanmerini
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Coralie Fontaine
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Pierre Gourdy
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Jean-François Arnal
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France
| | - Françoise Lenfant
- I2MC, Institut National de la Santé et de la Recherche Médicale (INSERM) U1297, Université de Toulouse 3 and CHU de Toulouse, Toulouse, France.
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36
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Thiebaut C, Vlaeminck-Guillem V, Trédan O, Poulard C, Le Romancer M. Non-genomic signaling of steroid receptors in cancer. Mol Cell Endocrinol 2021; 538:111453. [PMID: 34520815 DOI: 10.1016/j.mce.2021.111453] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Revised: 09/03/2021] [Accepted: 09/05/2021] [Indexed: 12/21/2022]
Abstract
Steroid receptors (SRs) are members of the nuclear receptor family, which are ligand-activated transcription factors. SRs regulate many physiological functions including development and reproduction, though they can also be involved in several pathologies, especially cancer. Highly controlled cellular responses to steroids involve transcriptional regulation (genomic activity) combined with direct activation of signaling cascades (non-genomic activity). Non-genomic signaling has been extensively studied in cancer, mainly in breast cancer for ER and PR, and prostate cancer for AR. Even though most of the studies have been conducted in cells, some of them have been confirmed in vivo, highlighting the relevance of this pathway in cancer. This review provides an overview of the current and emerging knowledge on non-genomic signaling with a focus on breast and prostate cancers and its clinical relevance. A thorough understanding of ER, PR, AR and GR non-genomic pathways may open new perspectives for the development of therapeutic strategies.
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Affiliation(s)
- Charlène Thiebaut
- Université de Lyon, F-69000, Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Virginie Vlaeminck-Guillem
- Université de Lyon, F-69000, Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Service de Biochimie Biologie Moléculaire Sud, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, F-69495, Pierre-Bénite, France
| | - Olivier Trédan
- Université de Lyon, F-69000, Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; Medical Oncology Department, Centre Léon Bérard, F-69000, Lyon, France
| | - Coralie Poulard
- Université de Lyon, F-69000, Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France
| | - Muriel Le Romancer
- Université de Lyon, F-69000, Lyon, France; Inserm U1052, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France; CNRS UMR5286, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France.
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Fiocchetti M, Bastari G, Cipolletti M, Leone S, Acconcia F, Marino M. The Peculiar Estrogenicity of Diethyl Phthalate: Modulation of Estrogen Receptor α Activities in the Proliferation of Breast Cancer Cells. TOXICS 2021; 9:237. [PMID: 34678933 PMCID: PMC8538674 DOI: 10.3390/toxics9100237] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/29/2022]
Abstract
Phthalates comprise a group of synthetic chemicals present in the environment because of their wide use as plasticizers and as additives in products for personal care. Among others, diethyl phthalate (DEP) is largely used in products for infants, children, and adults, in which its exposure has been correlated with an increased risk of breast cancer. The adverse health outcomes deriving from phthalate exposure have been associated with their activity as endocrine disruptors (EDCs) of the steroid and thyroid hormone signaling by affecting developmental and reproductive health, and even carcinogenicity. However, the estrogen disruptor activities of DEP are still controversial, and the mechanism at the root of the estrogenic-disrupting action of DEP remains to be clarified. Here, we evaluated the DEP mechanism of action on the activation status of estrogen receptor α (ERα) by analyzing the receptor's phosphorylation as well as both nuclear and extra-nuclear pathways triggered by the receptor to modulate the proliferation of breast cancer cells. Although DEP does not bind to ERα, our results suggest that this phthalate ester exerts multiple parallel interactions with ERα signaling and emphasize the importance to determine an appropriate battery of in vitro methods that will include specific molecular mechanisms involved in the endocrine disruption.
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Affiliation(s)
- Marco Fiocchetti
- Department of Science, University Roma Tre, Viale G. Marconi, 446, 00146 Rome, Italy; (G.B.); (M.C.); (S.L.); (F.A.)
| | | | | | | | | | - Maria Marino
- Department of Science, University Roma Tre, Viale G. Marconi, 446, 00146 Rome, Italy; (G.B.); (M.C.); (S.L.); (F.A.)
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Avellaneda E, Lim A, Moeller S, Marquez J, Escalante Cobb P, Zambrano C, Patel A, Sanchez V, Godde K, Broussard C. HPTE-Induced Embryonic Thymocyte Death and Alteration of Differentiation Is Not Rescued by ERα or GPER Inhibition but Is Exacerbated by Concurrent TCR Signaling. Int J Mol Sci 2021; 22:ijms221810138. [PMID: 34576301 PMCID: PMC8471014 DOI: 10.3390/ijms221810138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 09/07/2021] [Accepted: 09/13/2021] [Indexed: 11/16/2022] Open
Abstract
Organochlorine pesticides, such as DDT, methoxychlor, and their metabolites, have been characterized as endocrine disrupting chemicals (EDCs); suggesting that their modes of action involve interaction with or abrogation of endogenous endocrine function. This study examined whether embryonic thymocyte death and alteration of differentiation induced by the primary metabolite of methoxychlor, HPTE, rely upon estrogen receptor binding and concurrent T cell receptor signaling. Estrogen receptor inhibition of ERα or GPER did not rescue embryonic thymocyte death induced by HPTE or the model estrogen diethylstilbestrol (DES). Moreover, adverse effects induced by HPTE or DES were worsened by concurrent TCR and CD2 differentiation signaling, compared with EDC exposure post-signaling. Together, these data suggest that HPTE- and DES-induced adverse effects on embryonic thymocytes do not rely solely on ER alpha or GPER but may require both. These results also provide evidence of a potential collaborative signaling mechanism between TCR and estrogen receptors to mediate adverse effects on embryonic thymocytes, as well as highlight a window of sensitivity that modulates EDC exposure severity.
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Affiliation(s)
- Eddie Avellaneda
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Atalie Lim
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Sara Moeller
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Jacqueline Marquez
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Priscilla Escalante Cobb
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Cristina Zambrano
- Department of Pharmacology, School of Medicine, University of California San Diego, La Jolla, CA 92093, USA;
| | - Aaditya Patel
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - Victoria Sanchez
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
| | - K. Godde
- Department of Sociology/Anthropology, University of La Verne, La Verne, CA 91750, USA;
| | - Christine Broussard
- Department of Biology, University of La Verne, La Verne, CA 91750, USA; (E.A.); (A.L.); (S.M.); (J.M.); (P.E.C.); (A.P.); (V.S.)
- Correspondence:
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Peired AJ, Campi R, Angelotti ML, Antonelli G, Conte C, Lazzeri E, Becherucci F, Calistri L, Serni S, Romagnani P. Sex and Gender Differences in Kidney Cancer: Clinical and Experimental Evidence. Cancers (Basel) 2021; 13:cancers13184588. [PMID: 34572815 PMCID: PMC8466874 DOI: 10.3390/cancers13184588] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/07/2021] [Accepted: 09/08/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Kidney cancer is a frequent malignant tumor that accounts for approximately 5% of all cancer incidences. It affects both males and females, but males are twice as likely to develop kidney cancer than females. Evidence shows that this discrepancy takes root in individual differences, such as genetics or pathologies that affect the patient. It is then reflected in the clinical characteristics of the tumors, as males have larger and more aggressive tumors. Understanding the sex- and gender-based differences in kidney cancer is essential to be able to offer patients individualized medicine that would better cover their needs in terms of prevention, diagnosis and treatment. Abstract Sex and gender disparities have been reported for different types of non-reproductive cancers. Males are two times more likely to develop kidney cancer than females and have a higher death rate. These differences can be explained by looking at genetics and genomics, as well as other risk factors such as hypertension and obesity, lifestyle, and female sex hormones. Examination of the hormonal signaling pathways bring further insights into sex-related differences. Sex and gender-based disparities can be observed at the diagnostic, histological and treatment levels, leading to significant outcome difference. This review summarizes the current knowledge about sex and gender-related differences in the clinical presentation of patients with kidney cancer and the possible biological mechanisms that could explain these observations. Underlying sex-based differences may contribute to the development of sex-specific prognostic and diagnostic tools and the improvement of personalized therapies.
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Affiliation(s)
- Anna Julie Peired
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
- Correspondence:
| | - Riccardo Campi
- Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, 50134 Florence, Italy; (R.C.); (S.S.)
- Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Maria Lucia Angelotti
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
| | - Giulia Antonelli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
| | - Carolina Conte
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
| | - Elena Lazzeri
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
| | - Francesca Becherucci
- Nephrology and Dialysis Unit, Meyer Children’s University Hospital, Viale Pieraccini 24, 50139 Florence, Italy;
| | - Linda Calistri
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
| | - Sergio Serni
- Unit of Urological Robotic Surgery and Renal Transplantation, Careggi Hospital, University of Florence, 50134 Florence, Italy; (R.C.); (S.S.)
- Department of Experimental and Clinical Medicine, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Paola Romagnani
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale Morgagni 50, 50134 Florence, Italy; (M.L.A.); (G.A.); (C.C.); (E.L.); (L.C.); (P.R.)
- Nephrology and Dialysis Unit, Meyer Children’s University Hospital, Viale Pieraccini 24, 50139 Florence, Italy;
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40
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Zhao B, Ye X, Yang Y, Wang Y, Wang R, Pan X, Wang M. Knockdown of ER-α36 expression inhibits glioma proliferation, invasion and epithelial-to-mesenchymal transition. Anat Rec (Hoboken) 2021; 305:321-332. [PMID: 34331393 DOI: 10.1002/ar.24723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/30/2021] [Accepted: 05/07/2021] [Indexed: 12/15/2022]
Abstract
Estrogen receptor-α36 (ER-α36), a subtype of the estrogen receptor, is reported to play roles in tumorigenesis and tamoxifen resistance in several tumors, especially breast cancer. However, the role of ER-α36 in glioma proliferation and invasion remains unknown. Here, we explored the function of ER-α36 in glioma cells, using U87 and U251 cell lines. We found that ER-α36 was upregulated in glioma tissues compared to adjacent nontumor tissues. In U87 and U251 glioma cell lines, inhibition of ER-α36 expression by shRNA suppressed cell proliferation and invasion. In addition, the expression of an epithelial marker, ZO-1, was upregulated while that of one mesenchymal marker, N-cadherin, was downregulated with ER-α36 knockdown. We also found that inhibition of ER-α36 inactivated both PI3K/AKT and MEK/ERK signals. Taken together, these data indicated that overexpression of ER-α36 is associated with glioma proliferation and progression but that inhibition of ER-α36 leads to suppressed invasion and the epithelial-to-mesenchymal transition via PI3K/AKT and MEK/ERK pathway inactivation in glioma cells.
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Affiliation(s)
- Bowen Zhao
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China
| | - Xiang Ye
- Department of Neurology, Cadre Clinic, Qilu Hospital of Shandong University, Jinan, China
| | - Yuanyuan Yang
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China.,Prenatal Diagnosis Center, Jinan Maternity and Child Care Hospital, Jinan, China
| | - Yuxing Wang
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China.,Prenatal Diagnosis Center, Jinan Maternity and Child Care Hospital, Jinan, China
| | - Ru Wang
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China.,Prenatal Diagnosis Center, Jinan Maternity and Child Care Hospital, Jinan, China
| | - Xiaohua Pan
- Department of Breast and Thyroid surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Molin Wang
- Department of Genetics and Key Laboratory for Experimental Teratology of the Ministry of Education, School of Basic Medical Science, Shandong University, Jinan, China.,Prenatal Diagnosis Center, Jinan Maternity and Child Care Hospital, Jinan, China
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Single-cell immunoblotting resolves estrogen receptor-α isoforms in breast cancer. PLoS One 2021; 16:e0254783. [PMID: 34314438 PMCID: PMC8315538 DOI: 10.1371/journal.pone.0254783] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 03/28/2021] [Indexed: 12/18/2022] Open
Abstract
An array of isoforms of the nuclear estrogen receptor alpha (ER-α) protein contribute to heterogeneous response in breast cancer (BCa); yet, a single-cell analysis tool that distinguishes the full-length ER-α66 protein from the activation function-1 deficient ER-α46 isoform has not been reported. Specific detection of protein isoforms is a gap in single-cell analysis tools, as the de facto standard immunoassay requires isoform-specific antibody probes. Consequently, to scrutinize hormone response heterogeneity among BCa tumor cells, we develop a precision tool to specifically measure ER-α66, ER- α46, and eight ER-signaling proteins with single-cell resolution in the highly hetero-clonal MCF-7 BCa cell line. With a literature-validated pan-ER immunoprobe, we distinguish ER-α66 from ER-α46 in each individual cell. We identify ER-α46 in 5.5% of hormone-sensitive (MCF-7) and 4.2% of hormone-insensitive (MDA-MB-231) BCa cell lines. To examine whether the single-cell immunoblotting can capture cellular responses to hormones, we treat cells with tamoxifen and identify different sub-populations of ER-α46: (i) ER-α46 induces phospho-AKT at Ser473, (ii) S6-ribosomal protein, an upstream ER target, activates both ER-α66 and ER-α46 in MCF-7 cells, and (iii) ER-α46 partitions MDA-MB-231 subpopulations, which are responsive to tamoxifen. Unlike other single-cell immunoassays, multiplexed single-cell immunoblotting reports–in the same cell–tamoxifen effects on ER signaling proteins and on distinct isoforms of the ER-α protein.
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Notas G, Panagiotopoulos A, Vamvoukaki R, Kalyvianaki K, Kiagiadaki F, Deli A, Kampa M, Castanas E. ERα36-GPER1 Collaboration Inhibits TLR4/NFκB-Induced Pro-Inflammatory Activity in Breast Cancer Cells. Int J Mol Sci 2021; 22:ijms22147603. [PMID: 34299224 PMCID: PMC8303269 DOI: 10.3390/ijms22147603] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 07/06/2021] [Accepted: 07/09/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is important for the initiation and progression of breast cancer. We have previously reported that in monocytes, estrogen regulates TLR4/NFκB-mediated inflammation via the interaction of the Erα isoform ERα36 with GPER1. We therefore investigated whether a similar mechanism is present in breast cancer epithelial cells, and the effect of ERα36 expression on the classic 66 kD ERα isoform (ERα66) functions. We report that estrogen inhibits LPS-induced NFκB activity and the expression of downstream molecules TNFα and IL-6. In the absence of ERα66, ERα36 and GPER1 are both indispensable for this effect. In the presence of ERα66, ERα36 or GPER1 knock-down partially inhibits NFκB-mediated inflammation. In both cases, ERα36 overexpression enhances the inhibitory effect of estrogen on inflammation. We also verify that ERα36 and GPER1 physically interact, especially after LPS treatment, and that GPER1 interacts directly with NFκB. When both ERα66 and ERα36 are expressed, the latter acts as an inhibitor of ERα66 via its binding to estrogen response elements. We also report that the activation of ERα36 leads to the inhibition of breast cancer cell proliferation. Our data support that ERα36 is an inhibitory estrogen receptor that, in collaboration with GPER1, inhibits NFκB-mediated inflammation and ERα66 actions in breast cancer cells.
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Affiliation(s)
- George Notas
- Correspondence: ; Tel.: +30-2810-3945-56; Fax: +30-2810-3945-81
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Wang C, Zhang T, Wang K, Zhang S, Sun Q, Yang X. ER-α36 Promotes the Malignant Progression of Cervical Cancer Mediated by Estrogen via HMGA2. Front Oncol 2021; 11:712849. [PMID: 34336701 PMCID: PMC8317436 DOI: 10.3389/fonc.2021.712849] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/28/2021] [Indexed: 01/12/2023] Open
Abstract
Objectives Estrogen is proven to promote the malignant behaviors of many cancers via its receptors. Estrogen receptor alfa 36 (ER-α36) is a newly identified isoform of estrogen receptor alfa (ER-α), the role of ER-α36 in regulating the effects of estrogen and its potential impact on human cervical cancer is poorly understood. Methods Immunohistochemistry staining was used to evaluate the expression of ER-α36, estrogen receptor alfa 66 (ER-α66) and their prognostic values in cervical cancer. The effects of ER-α36 and ER-α66 on the proliferation and metastasis of cervical cancer were measured in vitro. A xenograft tumor assay was used to study the tumorigenesis role of ER-α36 in vivo. Furthermore, the functional gene at the downstream of ER-α36 was obtained via next-generation sequencing, and the biological functions of high mobility group A2 (HMGA2) in cervical cancer cells were investigated in vitro. Results ER-α36 was over-expressed in cervical cancer tissues and elevated ER-α36 expression was associated with poor prognosis in cervical cancer patients. High expression of ER-α36 promoted the proliferation, invasion and metastasis of cervical cancer cells mediated by estrogen, while silencing ER-α36 had the opposite effects. Further research showed that HMGA2 was a downstream target of ER-α36 in cervical cancer cells. The oncogenic effect of ER-α36 was attenuated after HMGA2 knockdown. Conclusions High expression of ER-α36 was correlated with a poor prognosis in cervical cancer by regulating HMGA2. ER-α36 could be a prognostic biomarker and a target for cervical cancer treatment.
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Affiliation(s)
- Chunyan Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Tianli Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Kun Wang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Shuo Zhang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
| | - Qing Sun
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Xingsheng Yang
- Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China
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Sahoo S, Mishra A, Kaur H, Hari K, Muralidharan S, Mandal S, Jolly MK. A mechanistic model captures the emergence and implications of non-genetic heterogeneity and reversible drug resistance in ER+ breast cancer cells. NAR Cancer 2021; 3:zcab027. [PMID: 34316714 PMCID: PMC8271219 DOI: 10.1093/narcan/zcab027] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/02/2021] [Accepted: 06/18/2021] [Indexed: 02/07/2023] Open
Abstract
Resistance to anti-estrogen therapy is an unsolved clinical challenge in successfully treating ER+ breast cancer patients. Recent studies have demonstrated the role of non-genetic (i.e. phenotypic) adaptations in tolerating drug treatments; however, the mechanisms and dynamics of such non-genetic adaptation remain elusive. Here, we investigate coupled dynamics of epithelial–mesenchymal transition (EMT) in breast cancer cells and emergence of reversible drug resistance. Our mechanism-based model for underlying regulatory network reveals that these two axes can drive one another, thus enabling non-genetic heterogeneity in a cell population by allowing for six co-existing phenotypes: epithelial-sensitive, mesenchymal-resistant, hybrid E/M-sensitive, hybrid E/M-resistant, mesenchymal-sensitive and epithelial-resistant, with the first two ones being most dominant. Next, in a population dynamics framework, we exemplify the implications of phenotypic plasticity (both drug-induced and intrinsic stochastic switching) and/or non-genetic heterogeneity in promoting population survival in a mixture of sensitive and resistant cells, even in the absence of any cell–cell cooperation. Finally, we propose the potential therapeutic use of mesenchymal–epithelial transition inducers besides canonical anti-estrogen therapy to limit the emergence of reversible drug resistance. Our results offer mechanistic insights into empirical observations on EMT and drug resistance and illustrate how such dynamical insights can be exploited for better therapeutic designs.
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Affiliation(s)
- Sarthak Sahoo
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Ashutosh Mishra
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Harsimran Kaur
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Kishore Hari
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Srinath Muralidharan
- Department of Biotechnology, Indian Institute of Technology Madras, Chennai 600036, India
| | - Susmita Mandal
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bangalore 560012, India
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45
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Juliansyah A, Rahman S, Indra I, Nelwan B, Prihantono P. Association of ERα-36 expression with the de novo resistance of tamoxifen in ER-positive breast cancer. Breast Dis 2021; 40:S123-S127. [PMID: 34057127 DOI: 10.3233/bd-219019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Approximately 70-80% of breast cancer express ER-alpha and hormonal therapies, given significant improvements in patient survival. About 50% of ER-positive breast cancer patients with advanced disease insensitive to tamoxifen treatment when diagnosed. Recent studies have shown that ERα-36 is a crucial factor in the resistance of tamoxifen. OBJECTIVE This study aims to determine the association between ERα-36 expression and de novo resistance of tamoxifen in patients with ER-positive breast cancer. METHODS This study was an observational study using a cross-sectional method and was conducted at Wahidin Sudirohusodo Hospital and Unhas Hospital. ERα-36 protein expression was assessed using an immunohistochemistry assay. The association of ERα-36 expression and resistance of tamoxifen was tested with the Chi-square test. RESULTS A total of 50 locally advanced breast cancer cases were included in this study, 22 cases (44%) had overexpression of ERα-36, and 28 cases (56%) had not, 24 cases (48%) had experience resistance to tamoxifen and 26 cases (52%) had not. There was a significant association between ERα-36 expressions and resistance of tamoxifen (p = 0.000). CONCLUSIONS There was an association between the expression of ER-α36 with de novo resistance of tamoxifen in ER-positive breast cancer. ER-α36 could act as a worth considering biomarker for de novo resistance of tamoxifen in therapeutic strategies.
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Affiliation(s)
- Amir Juliansyah
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Septiman Rahman
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Indra Indra
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Berti Nelwan
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Universitas Hasanuddin, Makassar, Indonesia
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46
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Rusidzé M, Adlanmérini M, Chantalat E, Raymond-Letron I, Cayre S, Arnal JF, Deugnier MA, Lenfant F. Estrogen receptor-α signaling in post-natal mammary development and breast cancers. Cell Mol Life Sci 2021; 78:5681-5705. [PMID: 34156490 PMCID: PMC8316234 DOI: 10.1007/s00018-021-03860-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 05/12/2021] [Accepted: 05/19/2021] [Indexed: 12/16/2022]
Abstract
17β-estradiol controls post-natal mammary gland development and exerts its effects through Estrogen Receptor ERα, a member of the nuclear receptor family. ERα is also critical for breast cancer progression and remains a central therapeutic target for hormone-dependent breast cancers. In this review, we summarize the current understanding of the complex ERα signaling pathways that involve either classical nuclear “genomic” or membrane “non-genomic” actions and regulate in concert with other hormones the different stages of mammary development. We describe the cellular and molecular features of the luminal cell lineage expressing ERα and provide an overview of the transgenic mouse models impacting ERα signaling, highlighting the pivotal role of ERα in mammary gland morphogenesis and function and its implication in the tumorigenic processes. Finally, we describe the main features of the ERα-positive luminal breast cancers and their modeling in mice.
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Affiliation(s)
- Mariam Rusidzé
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Marine Adlanmérini
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Elodie Chantalat
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - I Raymond-Letron
- LabHPEC et Institut RESTORE, Université de Toulouse, CNRS U-5070, EFS, ENVT, Inserm U1301, Toulouse, France
| | - Surya Cayre
- Department of Cell Biology and Cancer, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR144, Paris, France
| | - Jean-François Arnal
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France
| | - Marie-Ange Deugnier
- Department of Cell Biology and Cancer, Institut Curie, PSL Research University, Sorbonne University, CNRS UMR144, Paris, France
| | - Françoise Lenfant
- INSERM U1297, Institut Des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse - UPS, CHU, Toulouse, France.
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You KS, Yi YW, Cho J, Park JS, Seong YS. Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer. Pharmaceuticals (Basel) 2021; 14:589. [PMID: 34207383 PMCID: PMC8233743 DOI: 10.3390/ph14060589] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 12/13/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is a subset of breast cancer with aggressive characteristics and few therapeutic options. The lack of an appropriate therapeutic target is a challenging issue in treating TNBC. Although a high level expression of epidermal growth factor receptor (EGFR) has been associated with a poor prognosis among patients with TNBC, targeted anti-EGFR therapies have demonstrated limited efficacy for TNBC treatment in both clinical and preclinical settings. However, with the advantage of a number of clinically approved EGFR inhibitors (EGFRis), combination strategies have been explored as a promising approach to overcome the intrinsic resistance of TNBC to EGFRis. In this review, we analyzed the literature on the combination of EGFRis with other molecularly targeted therapeutics or conventional chemotherapeutics to understand the current knowledge and to provide potential therapeutic options for TNBC treatment.
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Affiliation(s)
- Kyu Sic You
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea;
- Graduate School of Convergence Medical Science, Dankook University, Cheonan 3116, Chungcheongnam-do, Korea
| | - Yong Weon Yi
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (J.C.)
| | - Jeonghee Cho
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (J.C.)
| | - Jeong-Soo Park
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea;
| | - Yeon-Sun Seong
- Department of Biochemistry, College of Medicine, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea;
- Graduate School of Convergence Medical Science, Dankook University, Cheonan 3116, Chungcheongnam-do, Korea
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Chungcheongnam-do, Korea; (Y.W.Y.); (J.C.)
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Hua Z, White J, Zhou J. Cancer stem cells in TNBC. Semin Cancer Biol 2021; 82:26-34. [PMID: 34147641 DOI: 10.1016/j.semcancer.2021.06.015] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 06/07/2021] [Accepted: 06/14/2021] [Indexed: 12/24/2022]
Abstract
Triple-negative breast cancer (TNBC) is a broad collection of breast cancer that tests negative for estrogen receptors (ER), progesterone receptors (PR), and excess human epidermal growth factor receptor 2 (HER2) protein. TNBC is considered to have poorer prognosis than other types of breast cancer because of a lack of effective therapeutic targets. The success of precision cancer therapies relies on the clarification of key molecular mechanisms that drive tumor growth and metastasis; however, TNBC is highly heterogeneous in terms of their cellular lineage composition and the molecular nature within each individual case. In particular, the rare and sometimes slow cycling cancer stem cells (CSCs) can provide effective means for TNBC to resist various treatments. Single cell analysis technologies, including single-cell RNA-seq (scRNA-seq) and proteomics, provide an avenue to unravel patient-level intratumoral heterogeneity by identifying CSCs populations, CSC biomarkers and the range of tumor microenvironment cellular constituents that contribute to tumor growth. This review discusses the emerging evidence for the role of CSCs in driving TNBC incidence and the therapeutic implications in manipulating molecular signaling against this rare cell population for the control of this deadly disease.
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Affiliation(s)
- Zhan Hua
- Department of General Surgery, China-Japan Friendship Hospital, Beijing, 100029, People's Republic of China
| | - Jason White
- Tuskegee University, Center for Cancer Research, Tuskegee, AL, 36830, USA
| | - Jianjun Zhou
- Research Center for Translational Medicine, Cancer Stem Cell Institute, East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
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Reyes-García J, Montaño LM, Carbajal-García A, Wang YX. Sex Hormones and Lung Inflammation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1304:259-321. [PMID: 34019274 DOI: 10.1007/978-3-030-68748-9_15] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Inflammation is a characteristic marker in numerous lung disorders. Several immune cells, such as macrophages, dendritic cells, eosinophils, as well as T and B lymphocytes, synthetize and release cytokines involved in the inflammatory process. Gender differences in the incidence and severity of inflammatory lung ailments including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), lung cancer (LC), and infectious related illnesses have been reported. Moreover, the effects of sex hormones on both androgens and estrogens, such as testosterone (TES) and 17β-estradiol (E2), driving characteristic inflammatory patterns in those lung inflammatory diseases have been investigated. In general, androgens seem to display anti-inflammatory actions, whereas estrogens produce pro-inflammatory effects. For instance, androgens regulate negatively inflammation in asthma by targeting type 2 innate lymphoid cells (ILC2s) and T-helper (Th)-2 cells to attenuate interleukin (IL)-17A-mediated responses and leukotriene (LT) biosynthesis pathway. Estrogens may promote neutrophilic inflammation in subjects with asthma and COPD. Moreover, the activation of estrogen receptors might induce tumorigenesis. In this chapter, we summarize the most recent advances in the functional roles and associated signaling pathways of inflammatory cellular responses in asthma, COPD, PF, LC, and newly occurring COVID-19 disease. We also meticulously deliberate the influence of sex steroids on the development and progress of these common and severe lung diseases.
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Affiliation(s)
- Jorge Reyes-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico.,Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA
| | - Luis M Montaño
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Abril Carbajal-García
- Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, CDMX, Mexico City, Mexico
| | - Yong-Xiao Wang
- Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
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50
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Cataldi M, Citro V, Resnati C, Manco F, Tarantino G. New Avenues for Treatment and Prevention of Drug-Induced Steatosis and Steatohepatitis: Much More Than Antioxidants. Adv Ther 2021; 38:2094-2113. [PMID: 33761100 PMCID: PMC8107075 DOI: 10.1007/s12325-021-01669-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/11/2021] [Indexed: 12/12/2022]
Abstract
Drug-induced lipid accumulation in the liver may induce two clinically relevant conditions, drug-induced steatosis (DIS) and drug-induced steatohepatitis (DISH). The list of drugs that may cause DIS or DISH is long and heterogeneous and includes therapeutically relevant molecules that cannot be easily replaced by less hepatotoxic medicines, therefore making specific strategies necessary for DIS/DISH prevention or treatment. For years, the only available tools to achieve these goals have been antioxidant drugs and free radical scavengers, which counteract drug-induced mitochondrial dysfunction but, unfortunately, have only limited efficacy. In the present review we illustrate how in vitro preclinical research unraveled new key players in the pathogenesis of specific forms of DISH, and how, in a few cases, proof of concept of the beneficial effects of their pharmacological modulation has been obtained in vivo in animal models of this condition. The key issue emerging from these studies is that, in selected cases, liver toxicity depends on mechanisms unrelated to those responsible for the desired, primary pharmacological effects of the toxic drug and, therefore, specific strategies can be designed to overcome steatogenicity without making the drug ineffective. In particular, the hepatotoxic drug could be given in combination with a second molecule intended to selectively antagonize its liver toxicity whilst, ideally, potentiating its desired pharmacological activity. Although most of the evidence that we discuss is from in vitro or animal models and will need to be further explored and validated in humans, it highlights new avenues to be pursued in order to improve the safety of steatogenic drugs.
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Affiliation(s)
- Mauro Cataldi
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Vincenzo Citro
- Department of General Medicine, "Umberto I" Hospital, Nocera Inferiore, SA, Italy
| | - Chiara Resnati
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Federica Manco
- Section of Pharmacology, Department of Neuroscience, Reproductive Sciences and Dentistry, "Federico II" University of Naples, Naples, Italy
| | - Giovanni Tarantino
- Department of Clinical Medicine and Surgery, "Federico II" University Medical School of Naples, Naples, Italy.
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