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Gummadi R, Nori LP, Pindiprolu SKSS, Dasari N, Ahmad Z, Km M. Nanomaterials for delivery of drugs and genes to disrupt notch signaling pathway in breast cancer. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04082-2. [PMID: 40392305 DOI: 10.1007/s00210-025-04082-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 03/20/2025] [Indexed: 05/22/2025]
Abstract
Breast cancer, marked by considerable heterogeneity and intricate molecular subgroups, poses substantial obstacles to therapy. Epithelial-mesenchymal transition (EMT) and the existence of tumor-initiating cells (TICs) facilitate treatment resistance, metastasis, and worse prognosis. The Notch signaling system has garnered significant interest for its involvement in promoting epithelial-mesenchymal transition (EMT), maintaining tumor-initiating cells (TIC), and facilitating cancer progression, especially in truculent subtypes such as triple-negative breast cancer (TNBC). Targeting the Notch system represents a promising therapeutic strategy; nevertheless, traditional inhibitors frequently encounter obstacles, including inadequate selectivity and bioavailability. Nanocarrier-based drug delivery systems provide novel therapeutic strategies to these difficulties by augmenting the targeted delivery of Notch inhibitors and enhancing therapeutic efficacy. Solid lipid nanoparticles (SLNs), polymeric nanoparticles, lipid-based nanocarriers, and micelles exhibit promise in delivering Notch inhibitors to neoplastic cells, altering the Notch signaling pathway, and surmounting drug resistance. This review examines recent breakthroughs in nanocarrier systems aimed at the Notch signaling pathway in breast cancer, highlighting the therapeutic potential of integrating nanomedicine with Notch inhibition to disrupt epithelial-mesenchymal transition (EMT), tumor-initiating cells (TICs), and metastasis, thereby enhancing clinical outcomes.
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Affiliation(s)
- Ramakrishna Gummadi
- School of Pharmacy, Aditya University, Surampalem, 533437, India
- Department of Pharmaceutics, Shri Vishnu College of Pharmacy, Bhimavaram, India
| | | | | | - Nagasen Dasari
- School of Pharmacy, Aditya University, Surampalem, 533437, India
| | - Zubair Ahmad
- Centre of Bee Research and Its Products, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
- Applied College, Mahala Campus, King Khalid University, P.O. Box 9004, Abha, 61413, Saudi Arabia
| | - Muhasina Km
- Department of Pharmaceutical Analysis, Prime College of Pharmacy, Erattayal, Kodumbu, Palakkad, Kerala, 678551, India
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Martinez-Marin D, Stroman GC, Fulton CJ, Pruitt K. Frizzled receptors: gatekeepers of Wnt signaling in development and disease. Front Cell Dev Biol 2025; 13:1599355. [PMID: 40376615 PMCID: PMC12078226 DOI: 10.3389/fcell.2025.1599355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Accepted: 04/21/2025] [Indexed: 05/18/2025] Open
Abstract
Frizzled (FZD) receptors are a subset of G-protein-coupled receptors (GPCRs), the largest class of human cell surface receptors and a major target of FDA-approved drugs. Activated by Wnt ligands, FZDs regulate key cellular processes such as proliferation, differentiation, and polarity, positioning them at the intersection of developmental biology and disease, including cancer. Despite their significance, FZD signaling remains incompletely understood, particularly in distinguishing receptor-specific roles across canonical and non-canonical Wnt pathways. Challenges include defining ligand-receptor specificity, elucidating signal transduction mechanisms, and understanding the influence of post translational modifications and the cellular context. Structural dynamics, receptor trafficking, and non-canonical signaling contributions also remain areas of active investigation. Recent advances in structural biology, transcriptomics, and functional genomics are beginning to address these gaps, while emerging therapeutic approaches-such as small-molecule modulators and antibodies-highlight the potential of FZDs as drug targets. This review synthesizes current insights into FZD receptor biology, examines ongoing controversies, and outlines promising directions for future research and therapeutic development.
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Affiliation(s)
| | | | | | - Kevin Pruitt
- Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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3
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Finger AM, Hendley AM, Figueroa D, Gonzalez H, Weaver VM. Tissue mechanics in tumor heterogeneity and aggression. Trends Cancer 2025:S2405-8033(25)00096-2. [PMID: 40307158 DOI: 10.1016/j.trecan.2025.04.004] [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: 08/27/2024] [Revised: 03/10/2025] [Accepted: 04/04/2025] [Indexed: 05/02/2025]
Abstract
Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.
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Affiliation(s)
- Anna-Marie Finger
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Liver Disease Research, Global Drug Discovery, Novo Nordisk A/S, Malov, Denmark
| | - Audrey Marie Hendley
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143
| | - Diego Figueroa
- Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA
| | - Hugo Gonzalez
- Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA 94143; Current address: Laboratory of Tumor Microenvironment and Metastasis, Centro Ciencia & Vida, Santiago, Chile
| | - Valerie Marie Weaver
- Center for Bioengineering and Tissue Regeneration, Department of Surgery, University of California, San Francisco, San Francisco, CA, USA 94143; Department of Radiation Oncology, Department of Bioengineering and Therapeutic Sciences, Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94143, USA.
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Zhang C, Xu S, Yin C, Hu S, Liu P. The role of the mTOR pathway in breast cancer stem cells (BCSCs): mechanisms and therapeutic potentials. Stem Cell Res Ther 2025; 16:156. [PMID: 40158191 PMCID: PMC11954216 DOI: 10.1186/s13287-025-04218-4] [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: 11/20/2024] [Accepted: 02/11/2025] [Indexed: 04/01/2025] Open
Abstract
Breast cancer remains the most frequently diagnosed cancer globally, exerting a profound impact on women's health and healthcare systems. Central to its pathogenesis and therapeutic resistance are breast cancer stem cells (BCSCs), which possess unique properties such as self-renewal, differentiation, and resistance to conventional therapies, contributing to tumor initiation, metastasis, and recurrence. This comprehensive review elucidates the pivotal role of the mechanistic target of rapamycin (mTOR) pathway in regulating BCSCs and its implications for breast cancer progression and treatment resistance. We explore the cellular mechanisms by which mTOR influences metastasis, metabolism, autophagy, and ferroptosis in BCSCs, highlighting its contribution to epithelial-to-mesenchymal transition (EMT), metabolic reprogramming, and survival under therapeutic stress. On a molecular level, mTOR interacts with key signaling pathways including PI3K/Akt, Notch, IGF-1R, AMPK, and TGF-β, as well as regulatory proteins and non-coding RNAs, orchestrating a complex network that sustains BCSC properties and mediates chemoresistance and radioresistance. The review further examines various therapeutic strategies targeting the mTOR pathway in BCSCs, encompassing selective PI3K/Akt/mTOR inhibitors, monoclonal antibodies, natural products, and innovative approaches such as nanoparticle-mediated drug delivery. Clinical trials investigating mTOR inhibitors like sirolimus and combination therapies with agents such as everolimus and trastuzumab are discussed, underscoring their potential in eradicating BCSCs and improving patient outcomes. Additionally, natural compounds and repurposed drugs offer promising adjunctive therapies by modulating mTOR activity and targeting BCSC-specific vulnerabilities. In conclusion, targeting the mTOR pathway presents a viable and promising avenue for enhancing breast cancer treatment efficacy by effectively eliminating BCSCs, reducing tumor recurrence, and improving overall patient survival. Continued research and clinical validation of mTOR-targeted therapies are essential to translate these insights into effective clinical interventions, ultimately advancing personalized cancer management and therapeutic outcomes for breast cancer patients.
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Affiliation(s)
- Chen Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Shu Xu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China
| | - Chuanzheng Yin
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Shaobo Hu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
| | - Pian Liu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, 430022, China.
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Huang J, Zhen W, Ma X, Ge S, Ma L. MiR-301b-3p targets and regulates EBF3 to impact the stem-like phenotype of breast cancer cells through glycolysis. J Clin Biochem Nutr 2025; 76:25-34. [PMID: 39896160 PMCID: PMC11782780 DOI: 10.3164/jcbn.23-131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 05/18/2024] [Indexed: 02/04/2025] Open
Abstract
BACKGROUND Cancer stem cells are essential for the development of tumors, their recurrence, metastasis, and resistance to treatment. Previous studies have shown that the silencing of EBF3 promotes the progression of malignant tumors, but its impact on the stem-like phenotype of tumor cells remains unexplored. Therefore, this work aims to investigate the influence of EBF3 on the stem-like phenotype of breast cancer (BC) cells and its underlying molecular mechanisms. METHODS Bioinformatics analysis was utilized to predict EBF3 and miR-301b-3p expression and their binding sites in BC tissues. qRT-PCR was conducted to assess EBF3 and miR-301b-3p expression in BC cells. Cell viability was assessed using CCK-8 assay, while sphere-forming ability was assayed by sphere formation experiments. Western blot analysis was employed to assess the expression of stem cell-related markers and proteins associated with the glycolysis metabolic pathway. ECAR experiments and analysis of glycolysis metabolite production were performed to evaluate cellular glycolysis capacity. Dual-luciferase reporter assays and RIP were utilized to validate the binding relationship between EBF3 and miR-301b-3p. RESULTS EBF3 was downregulated in BC tissues and cells, and overexpression of EBF3 repressed the glycolysis capacity of BC cells, thereby suppressing stem-like phenotype. Furthermore, miR-301b-3p was identified as a direct target of EBF3, and its expression was increased in BC. Cell experiments revealed that miR-301b-3p suppressed EBF3 expression, thereby promoting the glycolysis capacity and stem-like phenotype of BC cells. CONCLUSION miR-301b-3p enhanced glycolysis and promoted the stem-like phenotype of BC cells by targeting EBF3. These findings can offer new therapeutic approaches for BC.
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Affiliation(s)
- Jiankang Huang
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Weidong Zhen
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Xiaokai Ma
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Suxia Ge
- Department of Thyroid and Breast Surgery, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
| | - Ling Ma
- Department of Gynecology, Anhui No.2 Provincial People’s Hospital, 1868 Dangshan Road, North 2nd Ring Road, Yaohai District, Hefei City, Anhui Province, 230000, China
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Shen J, He Y, Li S, Chen H. Crosstalk of methylation and tamoxifen in breast cancer (Review). Mol Med Rep 2024; 30:180. [PMID: 39129315 PMCID: PMC11338244 DOI: 10.3892/mmr.2024.13304] [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: 06/02/2024] [Accepted: 07/23/2024] [Indexed: 08/13/2024] Open
Abstract
Tamoxifen is a widely used anti‑estrogen drug in the endocrine therapy of breast cancer (BC). It blocks estrogen signaling by competitively binding to estrogen receptor α (ERα), thereby inhibiting the growth of BC cells. However, with the long‑term application of tamoxifen, a subset of patients with BC have shown resistance to tamoxifen, which leads to low overall survival and progression‑free survival. The molecular mechanism of resistance is mainly due to downregulation of ERα expression and abnormal activation of the PI3K/AKT/mTOR signaling pathway. Moreover, the downregulation of targeted gene expression mediated by DNA methylation is an important regulatory mode to control protein expression. In the present review, methylation and tamoxifen are briefly introduced, followed by a focus on the effect of methylation on tamoxifen resistance and sensitivity. Finally, the clinical application of methylation for tamoxifen is described, including its use as a prognostic indicator. Finally, it is hypothesized that when methylation is used in combination with tamoxifen, it could recover the resistance of tamoxifen.
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Affiliation(s)
- Jin Shen
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Yan He
- Department of Neurology, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Shengpeng Li
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
| | - Huimin Chen
- Department of Rehabilitation, The Affiliated Zhuzhou Hospital of Xiangya Medical College, Central South University, Zhuzhou, Hunan 412000, P.R. China
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7
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Altriche N, Gallant S, Augustine TN, Xulu KR. Navigating the Intricacies of Tumor Heterogeneity: An Insight into Potential Prognostic Breast Cancer Biomarkers. Biomark Insights 2024; 19:11772719241256798. [PMID: 38895160 PMCID: PMC11185041 DOI: 10.1177/11772719241256798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 04/24/2024] [Indexed: 06/21/2024] Open
Abstract
Breast cancer is a heterogeneous disease with diverse histological and molecular subtypes. Luminal breast tumors are the most diagnosed subtype. In luminal breast cancer, hormone receptors (including ER, PR, HER2) play a diagnostic and prognostic role. Despite the effectiveness of endocrine therapy in luminal breast tumors, tumor recurrence and resistance occur, and this may highlight evolutionary strategies for survival driven by stemness. In this review we thus consider the association between estrogen signaling and stemness in mediating tumor processes. Many studies report stemness as one of the factors promoting tumor progression. Its association with estrogen signaling warrants further investigation and provides an opportunity for the identification of novel biomarkers which may be used for diagnostic, prognostic, and therapeutic purposes. Breast cancer stem cells have been characterized (CD44+ CD24-) and their role in promoting treatment resistance and tumor recurrence widely studied; however, the complexity of tumor progression which also involve microenvironmental factors suggests the existence of more varied cell phenotypes which mediate stemness and its role in tumor progression.
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Affiliation(s)
- Nastassia Altriche
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Simone Gallant
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Tanya Nadine Augustine
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
| | - Kutlwano Rekgopetswe Xulu
- School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, Gauteng, South Africa
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8
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Li H, Li J, Zhang Y, Zhao C, Ge J, Sun Y, Fu H, Li Y. The therapeutic effect of traditional Chinese medicine on breast cancer through modulation of the Wnt/β-catenin signaling pathway. Front Pharmacol 2024; 15:1401979. [PMID: 38783943 PMCID: PMC11111876 DOI: 10.3389/fphar.2024.1401979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 04/19/2024] [Indexed: 05/25/2024] Open
Abstract
Breast cancer, the most prevalent malignant tumor among women globally, is significantly influenced by the Wnt/β-catenin signaling pathway, which plays a crucial role in its initiation and progression. While conventional chemotherapy, the standard clinical treatment, suffers from significant drawbacks like severe side effects, high toxicity, and limited prognostic efficacy, Traditional Chinese Medicine (TCM) provides a promising alternative. TCM employs a multi-targeted therapeutic approach, which results in fewer side effects and offers a high potential for effective treatment. This paper presents a detailed analysis of the therapeutic impacts of TCM on various subtypes of breast cancer, focusing on its interaction with the Wnt/β-catenin signaling pathway. Additionally, it explores the effectiveness of both monomeric and compound forms of TCM in the management of breast cancer. We also discuss the potential of establishing biomarkers for breast cancer treatment based on key proteins within the Wnt/β-catenin signaling pathway. Our aim is to offer new insights into the prevention and treatment of breast cancer and to contribute to the standardization of TCM.
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Affiliation(s)
- Hongkun Li
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jiawei Li
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yifan Zhang
- College of Acupuncture-Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Chengcheng Zhao
- Experimental Teaching and Practical Training Center, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Jun Ge
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yujiao Sun
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hui Fu
- College of Integrated Chinese and Western Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yingpeng Li
- College of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Ray SK, Mukherjee S. Breast cancer stem cells as novel biomarkers. Clin Chim Acta 2024; 557:117855. [PMID: 38453050 DOI: 10.1016/j.cca.2024.117855] [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: 01/31/2024] [Revised: 03/02/2024] [Accepted: 03/04/2024] [Indexed: 03/09/2024]
Abstract
Breast cancer is the most common cancer and the leading cause of mortality worldwide. Despite advancements in detection and treatment, it remains a major cause of cancer-related deaths in women. Breast cancer stem cells (BCSCs) are a crucial group of cells responsible for carcinogenesis, metastasis, medication resistance, and tumor recurrence. Identifying and understanding their molecular pathways is essential for developing effective breast cancer therapy. BCSCs are responsible for tumor genesis, development, metastasis, treatment resistance, and recurrence. Biomarkers are essential tools for identifying high-risk patients, improving diagnostic accuracy, developing follow-up programs, assessing treatment susceptibility, and predicting prognostic outcomes. Stem cell intervention therapy can provide specialized tools for precision therapy. Biomarker analysis in cancer patients is crucial to identify cells associated with disease progression and post-therapeutic relapse. However, negative post-therapeutic impacts can enhance cancer stemness by boosting BCSCs plasticity phenotypes, activating stemness pathways in non-BCSCs, and promoting senescence escape, leading to tumor relapse and metastasis. Despite the advancements in precision medicine, challenges persist in identifying stem cell markers, limiting the number of eligible patients for treatment. The diversity of biomedical research hinders the development of individualization-based preventative, monitoring, and treatment strategies, especially in oncology. Integrating and interpreting clinical and scientific data remains challenging. The development of stem cell-related indicators could significantly improve disease precision, enabling stem cell-targeted therapy and personalized treatment plans, although BCSCs are promising for breast cancer treatment optimization, serving as biomarkers for current therapy modalities. This summary discusses recent advancements in breast cancer stem cell research, including biomarkers, identification methods, molecular mechanisms, and tools for studying their biological origin and lineage development for precision medicine.
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Affiliation(s)
- Suman Kumar Ray
- Independent Researcher, Bhopal, Madhya Pradesh 462020, India
| | - Sukhes Mukherjee
- Department of Biochemistry, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh 462020, India.
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Waldum H, Slupphaug G. Correctly identifying the cells of origin is essential for tailoring treatment and understanding the emergence of cancer stem cells and late metastases. Front Oncol 2024; 14:1369907. [PMID: 38660133 PMCID: PMC11040596 DOI: 10.3389/fonc.2024.1369907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024] Open
Abstract
Malignancy manifests itself by deregulated growth and the ability to invade surrounding tissues or metastasize to other organs. These properties are due to genetic and/or epigenetic changes, most often mutations. Many aspects of carcinogenesis are known, but the cell of origin has been insufficiently focused on, which is unfortunate since the regulation of its growth is essential to understand the carcinogenic process and guide treatment. Similarly, the concept of cancer stem cells as cells having the ability to stop proliferation and rest in a state of dormancy and being resistant to cytotoxic drugs before "waking up" and become a highly malignant tumor recurrence, is not fully understood. Some tumors may recur after decades, a phenomenon probably also connected to cancer stem cells. The present review shows that many of these questions are related to the cell of origin as differentiated cells being long-term stimulated to proliferation.
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Affiliation(s)
- Helge Waldum
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
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Ali K, Nabeel M, Mohsin F, Iqtedar M, Islam M, Rasool MF, Hashmi FK, Hussain SA, Saeed H. Recent developments in targeting breast cancer stem cells (BCSCs): a descriptive review of therapeutic strategies and emerging therapies. Med Oncol 2024; 41:112. [PMID: 38592510 DOI: 10.1007/s12032-024-02347-z] [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: 01/12/2024] [Accepted: 02/27/2024] [Indexed: 04/10/2024]
Abstract
Despite recent advancements in the diagnosis and treatment of breast cancer (BC), patient outcomes in terms of survival, recurrence, and disease progression remain suboptimal. A significant factor contributing to these challenges is the cellular heterogeneity within BC, particularly the presence of breast cancer stem cells (BCSCs). These cells are thought to serve as the clonogenic nexus for new tumor growth, owing to their hierarchical organization within the tumor. This descriptive review focuses on the evolving strategies to target BCSCs, which have become a pivotal aspect of therapeutic development. We explore a variety of approaches, including targeting specific tumor surface markers (CD133 and CD44), transporters, heat shock proteins, and critical signaling pathways like Notch, Akt, Hedgehog, KLF4, and Wnt/β-catenin. Additionally, we discuss the modulation of the tumor microenvironment through the CXCR-12/CXCR4 axis, manipulation of pH levels, and targeting hypoxia-inducible factors, vascular endothelial growth factor, and CXCR1/2 receptors. Further, this review focuses on the roles of microRNA expression, strategies to induce apoptosis and differentiation in BCSCs, dietary interventions, dendritic cell vaccination, oncolytic viruses, nanotechnology, immunotherapy, and gene therapy. We particularly focused on studies reporting identification of BCSCs, their unique properties and the efficacy of various therapeutic modalities in targeting these cells. By dissecting these approaches, we aim to provide insights into the complex landscape of BC treatment and the potential pathways for improving patient outcomes through targeted BCSC therapies.
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Affiliation(s)
- Khubaib Ali
- Department of Clinical Pharmacy, Akhtar Saeed College of Pharmaceutical Sciences, Bahria Town, Lahore, Pakistan
- Department Clinical Oncology Pharmacy, Cancer Care Hospital & Research Centre, Lahore, Pakistan
| | - Muhammad Nabeel
- Department of Clinical Pharmacy, Akhtar Saeed College of Pharmaceutical Sciences, Bahria Town, Lahore, Pakistan
- Department Clinical Oncology Pharmacy, Cancer Care Hospital & Research Centre, Lahore, Pakistan
| | - Fatima Mohsin
- Department of Biological Sciences, KAM School of Life Sciences, Forman Christian College (A Chartered University), Lahore, Pakistan
| | - Mehwish Iqtedar
- Department of Bio-Technology, Lahore College for Women University, Jail Road, Lahore, Pakistan
| | - Muhammad Islam
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan
| | | | - Furqan K Hashmi
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan
| | | | - Hamid Saeed
- Department of Pharmaceutics, College of Pharmacy, University of the Punjab, Allama Iqbal Campus, Lahore, Pakistan.
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12
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Xavier PL, Marção M, Simões RL, Job MEG, de Francisco Strefezzi R, Fukumasu H, Malta TM. Machine learning determines stemness associated with simple and basal-like canine mammary carcinomas. Heliyon 2024; 10:e26714. [PMID: 38439848 PMCID: PMC10909659 DOI: 10.1016/j.heliyon.2024.e26714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 02/19/2024] [Indexed: 03/06/2024] Open
Abstract
Simple and complex carcinomas are the most common type of malignant Canine Mammary Tumors (CMTs), with simple carcinomas exhibiting aggressive behavior and poorer prognostic. Stemness is an ability associated with cancer initiation, malignancy, and therapeutic resistance, but is still few elucidated in canine mammary tumor subtypes. Here, we first validated, using CMT samples, a previously published canine one-class logistic regression machine learning algorithm (OCLR) to predict stemness (mRNAsi) in canine cancer cells. Then, using the canine mRNAsi, we observed that simple carcinomas exhibit higher stemness than complex carcinomas and other histological subtypes. Also, we confirmed that stemness is higher and associated with basal-like CMTs and with NMF2 metagene signature, a tumor-specific DNA-repair metagene signature. Using correlation analysis, we selected the top 50 genes correlated with higher stemness, and the top 50 genes correlated with lower stemness and further performed a gene set enrichment analysis to observe the biological processes enriched for these genes. Finally, we suggested two promise stemness-associated targets in CMTs, POLA2 and APEX1, especially in simple carcinomas. Thus, our work elucidates stemness as a potential mechanism behind the aggressiveness and development of canine mammary tumors, especially in simple carcinomas, describing evidence of a promising strategy to target this disease.
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Affiliation(s)
- Pedro L.P. Xavier
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, São Paulo, Brazil
| | - Maycon Marção
- Cancer Epigenomics Laboratory, Department of Clinical Analysis, Toxicology and Food Sciences, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Renan L.S. Simões
- Cancer Epigenomics Laboratory, Department of Clinical Analysis, Toxicology and Food Sciences, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Maria Eduarda G. Job
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, São Paulo, Brazil
| | - Ricardo de Francisco Strefezzi
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, São Paulo, Brazil
| | - Heidge Fukumasu
- Laboratory of Comparative and Translational Oncology (LOCT), Department of Veterinary Medicine, Faculdade de Zootecnia e Engenharia de Alimentos, Universidade de São Paulo, Pirassununga, São Paulo, Brazil
| | - Tathiane M. Malta
- Cancer Epigenomics Laboratory, Department of Clinical Analysis, Toxicology and Food Sciences, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil
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13
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Guha A, Goswami KK, Sultana J, Ganguly N, Choudhury PR, Chakravarti M, Bhuniya A, Sarkar A, Bera S, Dhar S, Das J, Das T, Baral R, Bose A, Banerjee S. Cancer stem cell-immune cell crosstalk in breast tumor microenvironment: a determinant of therapeutic facet. Front Immunol 2023; 14:1245421. [PMID: 38090567 PMCID: PMC10711058 DOI: 10.3389/fimmu.2023.1245421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 10/25/2023] [Indexed: 12/18/2023] Open
Abstract
Breast cancer (BC) is globally one of the leading killers among women. Within a breast tumor, a minor population of transformed cells accountable for drug resistance, survival, and metastasis is known as breast cancer stem cells (BCSCs). Several experimental lines of evidence have indicated that BCSCs influence the functionality of immune cells. They evade immune surveillance by altering the characteristics of immune cells and modulate the tumor landscape to an immune-suppressive type. They are proficient in switching from a quiescent phase (slowly cycling) to an actively proliferating phenotype with a high degree of plasticity. This review confers the relevance and impact of crosstalk between immune cells and BCSCs as a fate determinant for BC prognosis. It also focuses on current strategies for targeting these aberrant BCSCs that could open avenues for the treatment of breast carcinoma.
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Affiliation(s)
- Aishwarya Guha
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | | | - Jasmine Sultana
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Nilanjan Ganguly
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Pritha Roy Choudhury
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Mohona Chakravarti
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Avishek Bhuniya
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Anirban Sarkar
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Saurav Bera
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Sukanya Dhar
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Juhina Das
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Tapasi Das
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Rathindranath Baral
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
| | - Anamika Bose
- Department of Pharmaceutical Technology Biotechnology National Institute of Pharmaceutical Education and Research (NIPER) Sahibzada Ajit Singh (S.A.S.) Nagar, Mohali, Punjab, India
| | - Saptak Banerjee
- Department of Immunoregulation and Immunodiagnostics, Chittaranjan National Cancer Institute, Kolkata, India
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14
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Miret NV, Pontillo CA, Buján S, Chiappini FA, Randi AS. Mechanisms of breast cancer progression induced by environment-polluting aryl hydrocarbon receptor agonists. Biochem Pharmacol 2023; 216:115773. [PMID: 37659737 DOI: 10.1016/j.bcp.2023.115773] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/23/2023] [Accepted: 08/30/2023] [Indexed: 09/04/2023]
Abstract
Breast cancer is the most common invasive malignancy among women worldwide and constitutes a complex and heterogeneous disease. Interest has recently grown in the role of the aryl hydrocarbon receptor (AhR) in breast cancer and the contribution of environment-polluting AhR agonists. Here, we present a literature review addressing AhR ligands, including pesticides hexachlorobenzene and chlorpyrifos, polycyclic aromatic hydrocarbons, polychlorinated dibenzo-p-dioxins and dibenzofurans, polychlorinated biphenyls, parabens, and phthalates. The objectives of this review are a) to summarize recent original experimental, preclinical, and clinical studies on the biological mechanisms of AhR agonists which interfere with the regulation of breast endocrine functions, and b) to examine the biological effects of AhR ligands and their impact on breast cancer development and progression. We discuss biological mechanisms of action in cell viability, cell cycle, proliferation, epigenetic changes, epithelial to mesenchymal transition, and cell migration and invasion. In addition, we examine the effects of AhR ligands on angiogenic processes, metastasis, chemoresistance, and stem cell renewal. We conclude that exposure to AhR agonists stimulates pathways that promote breast cancer development and may contribute to tumor progression. Given the massive use of industrial and agricultural chemicals, ongoing evaluation of their effects in laboratory assays and preclinical studies in breast cancer at environmentally relevant doses is deemed essential. Likewise, awareness should be raised in the population regarding the most harmful toxicants to eradicate or minimize their use.
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Affiliation(s)
- Noelia V Miret
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Físico-Matemática, Laboratorio de Radioisótopos, Junín 954, 1er subsuelo (CP1113), Buenos Aires, Argentina.
| | - Carolina A Pontillo
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina
| | - Sol Buján
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina
| | - Florencia A Chiappini
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina
| | - Andrea S Randi
- Universidad de Buenos Aires, Facultad de Medicina, Departamento de Bioquímica Humana, Laboratorio de Efectos Biológicos de Contaminantes Ambientales, Paraguay 2155, Piso 5, (CP 1121), Buenos Aires, Argentina.
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15
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Bobbitt JR, Seachrist DD, Keri RA. Chromatin Organization and Transcriptional Programming of Breast Cancer Cell Identity. Endocrinology 2023; 164:bqad100. [PMID: 37394919 PMCID: PMC10370366 DOI: 10.1210/endocr/bqad100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 06/26/2023] [Accepted: 06/28/2023] [Indexed: 07/04/2023]
Abstract
The advent of sequencing technologies for assessing chromosome conformations has provided a wealth of information on the organization of the 3-dimensional genome and its role in cancer progression. It is now known that changes in chromatin folding and accessibility can promote aberrant activation or repression of transcriptional programs that can drive tumorigenesis and progression in diverse cancers. This includes breast cancer, which comprises several distinct subtypes defined by their unique transcriptomes that dictate treatment response and patient outcomes. Of these, basal-like breast cancer is an aggressive subtype controlled by a pluripotency-enforcing transcriptome. Meanwhile, the more differentiated luminal subtype of breast cancer is driven by an estrogen receptor-dominated transcriptome that underlies its responsiveness to antihormone therapies and conveys improved patient outcomes. Despite the clear differences in molecular signatures, the genesis of each subtype from normal mammary epithelial cells remains unclear. Recent technical advances have revealed key distinctions in chromatin folding and organization between subtypes that could underlie their transcriptomic and, hence, phenotypic differences. These studies also suggest that proteins controlling particular chromatin states may be useful targets for treating aggressive disease. In this review, we explore the current state of understanding of chromatin architecture in breast cancer subtypes and its potential role in defining their phenotypic characteristics.
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Affiliation(s)
- Jessica R Bobbitt
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Darcie D Seachrist
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
| | - Ruth A Keri
- Department of Cancer Biology, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
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16
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Sakibuzzaman M, Mahmud S, Afroze T, Fathma S, Zakia UB, Afroz S, Zafar F, Hossain M, Barua A, Akter S, Chowdhury HI, Ahsan E, Eshan SH, Fariza TT. Pathology of breast cancer metastasis and a view of metastasis to the brain. Int J Neurosci 2023; 133:544-554. [PMID: 34044732 DOI: 10.1080/00207454.2021.1935929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 05/17/2021] [Accepted: 05/19/2021] [Indexed: 02/07/2023]
Abstract
Despite the advances in diagnosis and management of breast cancer, metastasis has been responsible for the staggering percentage of breast cancer-related death. Mortality threat can be explained mostly by the lack of proper understanding of the diversity of pathological features and underlying mechanism of breast cancer metastasis and effective targeted therapy. Breast cancer stem cells (BCSCs) are the potential source of tumor cells spread to distant organs. BCSCs targeted therapy can suppress the breast cancer progression to metastasis. Spreading of tumor cells to the bone, lung, liver, and brain occurs through a distinct non-random process; called metastasis organotropism. Recently, brain metastasis in breast cancer patients has been detected more frequently, causing a significant clinical burden. BRCA1 and BRCA2 associated breast cancers carry a remarkably higher propensity of CNS metastasis. BRCA1 and BRCA2 associated breast cancers commonly have the propensity to be the triple-negative (TN) and hormone receptors (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative molecular subtypes, respectively. Regardless of molecular subtypes, metastasis is most commonly evident at the bone. Heterogeneity is a critical pathological feature, leads to therapeutic resistance. BCSCs, biomarkers expression patterns, and mutations contribute to heterogeneity. In this paper, we discuss crucial pathological features of breast cancer metastasis, emphasizing metastasis organotropism and heterogeneity; and mechanisms of breast cancer metastasis, highlighting the pathways of metastasis to the brain. We consider that this paper reinforces future research areas and benefits the general readers, physicians, and researchers to identify potential areas to develop targeted therapies.
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Affiliation(s)
- Md Sakibuzzaman
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Shahriar Mahmud
- Sher-E-Bangla Medical College and Hospital, Barisal, Bangladesh
| | | | - Sawsan Fathma
- Bangladesh Medical College and Hospital, Dhaka, Bangladesh
| | | | - Sabrina Afroz
- Faridpur Medical College and Hospital, Faridpur, Bangladesh
| | - Farzina Zafar
- Shaheed Suhrawardy Medical College and Hospital, Dhaka, Bangladesh
| | - Maksuda Hossain
- Biodesign Institute, Arizona State University, Tempe, AZ, USA
| | - Amit Barua
- Institute of Applied Health Sciences, Chattogram, Bangladesh
| | - Sabiha Akter
- Sher-E-Bangla Medical College and Hospital, Barisal, Bangladesh
| | | | - Eram Ahsan
- Medical College for Women and Hospital, Dhaka, Bangladesh
| | - Shayet Hossain Eshan
- Department of Internal Medicine, Amita Health Saint Joseph Hospital Chicago, Chicago, IL, USA
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17
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An Updated Review on Recent Advances in the Usage of Novel Therapeutic Peptides for Breast Cancer Treatment. Int J Pept Res Ther 2023. [DOI: 10.1007/s10989-023-10503-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
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18
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Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells 2023; 12:cells12050720. [PMID: 36899854 PMCID: PMC10001180 DOI: 10.3390/cells12050720] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.
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19
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The Role of Autophagy in Breast Cancer Metastasis. Biomedicines 2023; 11:biomedicines11020618. [PMID: 36831154 PMCID: PMC9953203 DOI: 10.3390/biomedicines11020618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 02/07/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Patient morbidity and mortality is significantly increased in metastatic breast cancer. The metastasis process of breast cancer is very complicated and is delicately controlled by various factors. Autophagy is one of the important regulatory factors affecting metastasis in breast cancer by engaging in cell mobility, metabolic adaptation, tumor dormancy, and cancer stem cells. Here, we discuss the effects of autophagy on metastasis in breast cancer and assess the potential use of autophagy modulators for metastasis treatment.
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20
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Casasent AK, Almekinders MM, Mulder C, Bhattacharjee P, Collyar D, Thompson AM, Jonkers J, Lips EH, van Rheenen J, Hwang ES, Nik-Zainal S, Navin NE, Wesseling J. Learning to distinguish progressive and non-progressive ductal carcinoma in situ. Nat Rev Cancer 2022; 22:663-678. [PMID: 36261705 DOI: 10.1038/s41568-022-00512-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/07/2022] [Indexed: 02/07/2023]
Abstract
Ductal carcinoma in situ (DCIS) is a non-invasive breast neoplasia that accounts for 25% of all screen-detected breast cancers diagnosed annually. Neoplastic cells in DCIS are confined to the ductal system of the breast, although they can escape and progress to invasive breast cancer in a subset of patients. A key concern of DCIS is overtreatment, as most patients screened for DCIS and in whom DCIS is diagnosed will not go on to exhibit symptoms or die of breast cancer, even if left untreated. However, differentiating low-risk, indolent DCIS from potentially progressive DCIS remains challenging. In this Review, we summarize our current knowledge of DCIS and explore open questions about the basic biology of DCIS, including those regarding how genomic events in neoplastic cells and the surrounding microenvironment contribute to the progression of DCIS to invasive breast cancer. Further, we discuss what information will be needed to prevent overtreatment of indolent DCIS lesions without compromising adequate treatment for high-risk patients.
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Affiliation(s)
- Anna K Casasent
- Department of Genetics, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Charlotta Mulder
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | | | | | - Jos Jonkers
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Esther H Lips
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Jacco van Rheenen
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands
| | | | - Serena Nik-Zainal
- Department of Medical Genetics, University of Cambridge, Cambridge, UK
| | - Nicholas E Navin
- Department of Genetics, MD Anderson Cancer Center, Houston, TX, USA
- Department of Bioinformatics, MD Anderson Cancer Center, Houston, TX, USA
| | - Jelle Wesseling
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, Netherlands.
- Department of Pathology, Leiden University Medical Center, Leiden, Netherlands.
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21
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Serrano-Quintero A, Sequeda-Juárez A, Pérez-Hernández CA, Sosa-Delgado SM, Mendez-Tenorio A, Ramón-Gallegos E. Immunogenic analysis of epitope-based vaccine candidate induced by photodynamic therapy in MDA-MB-231 triple-negative breast cancer cells. Photodiagnosis Photodyn Ther 2022; 40:103174. [PMID: 36602069 DOI: 10.1016/j.pdpdt.2022.103174] [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: 08/05/2022] [Revised: 09/20/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND Photodynamic therapy (PDT) is used to treat tumors through selective cytotoxic effects. PDT induces damage-associated molecular patterns (DAMPs) expression, which can cause an immunogenic death cell (IDC). In this study we identified potential immunogenic epitopes generated by PDT on triple-negative breast cancer cell line (MDA-MB-231). METHODS MDA-MB-231 cells were exposed to PDT using ALA (160 µg/mL)/630 nm at 8 J/cm2. Membrane proteins were extracted and separated by 2D PAGE. Proteins overexpressed were identified by LC-MS/MS and analyzed in silico through a peptide-HLA docking in order to identify the epitopes with more immunogenicity and antigenicity properties, as well as lower allergenicity and toxicity activity. The selected peptides were evaluated in response to macrophage activation and cytokine release by flow cytometry. RESULTS Differential proteins were overexpressed in the cells treated with PDT. A group of 16 peptides were identified from them, established in a rigorous selection by measuring antigenicity, immunogenicity, allergenicity, and toxicity in silico. The final selection was based on molecular dynamics, where 2 peptides showed the highest stability regarding to the RMSD value. These peptides were obtained from the proteins calreticulin and HSP90. The cytokine analysis evidenced macrophage activation by the releasing of TNF. CONCLUSION Two peptides were identified from calreticulin and HSP90; proteins induced by PDT in MDA-MB-231 cells. Both epitopes showed immunogenic potential as a peptide-based vaccine for triple-negative breast cancer.
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Affiliation(s)
- Alina Serrano-Quintero
- Laboratorio de Citopatología Ambiental, ENCB, Instituto Politécnico Nacional (IPN), Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda. Manuel Stampa, Col. Zacatenco. Alcaldia Gustavo A. Madero, Mexico City C.P. 07738, Mexico
| | - Alfonso Sequeda-Juárez
- Laboratorio de Citopatología Ambiental, ENCB, Instituto Politécnico Nacional (IPN), Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda. Manuel Stampa, Col. Zacatenco. Alcaldia Gustavo A. Madero, Mexico City C.P. 07738, Mexico
| | - C Angélica Pérez-Hernández
- Laboratorio de Citopatología Ambiental, ENCB, Instituto Politécnico Nacional (IPN), Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda. Manuel Stampa, Col. Zacatenco. Alcaldia Gustavo A. Madero, Mexico City C.P. 07738, Mexico
| | - Sara M Sosa-Delgado
- Laboratorio de Citopatología Ambiental, ENCB, Instituto Politécnico Nacional (IPN), Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda. Manuel Stampa, Col. Zacatenco. Alcaldia Gustavo A. Madero, Mexico City C.P. 07738, Mexico
| | - Alfonso Mendez-Tenorio
- Laboratorio de Bioinformática y Biotecnología Genómica, Departamento de Bioquímica, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City 11340, Mexico
| | - Eva Ramón-Gallegos
- Laboratorio de Citopatología Ambiental, ENCB, Instituto Politécnico Nacional (IPN), Campus Zacatenco, Calle Wilfrido Massieu Esquina Cda. Manuel Stampa, Col. Zacatenco. Alcaldia Gustavo A. Madero, Mexico City C.P. 07738, Mexico.
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22
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Ambrosio MR, Mosca G, Migliaccio T, Liguoro D, Nele G, Schonauer F, D’Andrea F, Liotti F, Prevete N, Melillo RM, Reale C, Ambrosino C, Miele C, Beguinot F, D’Esposito V, Formisano P. Glucose Enhances Pro-Tumorigenic Functions of Mammary Adipose-Derived Mesenchymal Stromal/Stem Cells on Breast Cancer Cell Lines. Cancers (Basel) 2022; 14:5421. [PMID: 36358839 PMCID: PMC9655059 DOI: 10.3390/cancers14215421] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 10/26/2022] [Accepted: 10/31/2022] [Indexed: 10/13/2023] Open
Abstract
Adiposity and diabetes affect breast cancer (BC) progression. We addressed whether glucose may affect the interaction between mammary adipose tissue-derived mesenchymal stromal/stem cells (MAT-MSCs) and BC cells. Two-dimensional co-cultures and spheroids were established in 25 mM or 5.5 mM glucose (High Glucose-HG or Low Glucose-LG) by using MAT-MSCs and MCF7 or MDA-MB231 BC cells. Gene expression was measured by qPCR, while protein levels were measured by cytofluorimetry and ELISA. CD44high/CD24low BC stem-like sub-population was quantified by cytofluorimetry. An in vivo zebrafish model was assessed by injecting spheroid-derived labeled cells. MAT-MSCs co-cultured with BC cells showed an inflammatory/senescent phenotype with increased abundance of IL-6, IL-8, VEGF and p16INK4a, accompanied by altered levels of CDKN2A and LMNB1. BC cells reduced multipotency and increased fibrotic features modulating OCT4, SOX2, NANOG, αSMA and FAP in MAT-MSCs. Of note, these co-culture-mediated changes in MAT-MSCs were partially reverted in LG. Only in HG, MAT-MSCs increased CD44high/CD24low MCF7 sub-population and promoted their ability to form mammospheres. Injection in zebrafish embryos of HG spheroid-derived MCF7 and MAT-MSCs was followed by a significant cellular migration and caudal dissemination. Thus, MAT-MSCs enhance the aggressiveness of BC cells in a HG environment.
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Affiliation(s)
- Maria Rosaria Ambrosio
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
| | - Giusy Mosca
- Department of Translational Medicine, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Teresa Migliaccio
- Department of Translational Medicine, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Domenico Liguoro
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
| | - Gisella Nele
- Department of Public Health, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Fabrizio Schonauer
- Department of Public Health, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Francesco D’Andrea
- Department of Public Health, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Federica Liotti
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Nella Prevete
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
- Department of Translational Medicine, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Rosa Marina Melillo
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Carla Reale
- Institute of Genetic Research “G. Salvatore” Biogem, Via Camporeale, 83031 Ariano Irpino, Italy
| | - Concetta Ambrosino
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
- Institute of Genetic Research “G. Salvatore” Biogem, Via Camporeale, 83031 Ariano Irpino, Italy
- Department of Science and Technology, University of Sannio, Via De Sanctis, 82100 Benevento, Italy
| | - Claudia Miele
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
| | - Francesco Beguinot
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
- Department of Translational Medicine, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
| | - Vittoria D’Esposito
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
| | - Pietro Formisano
- URT “Genomic of Diabetes”, Institute for Experimental Endocrinology and Oncology “G. Salvatore”, National Research Council (IEOS-CNR), Via Pansini 5, 80131 Naples, Italy
- Department of Translational Medicine, University of Naples “Federico II”, Via Pansini 5, 80131 Naples, Italy
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23
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Ingthorsson S, Traustadottir GA, Gudjonsson T. Cellular Plasticity and Heterotypic Interactions during Breast Morphogenesis and Cancer Initiation. Cancers (Basel) 2022; 14:cancers14215209. [PMID: 36358627 PMCID: PMC9654604 DOI: 10.3390/cancers14215209] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/19/2022] [Accepted: 10/20/2022] [Indexed: 12/01/2022] Open
Abstract
Simple Summary This review aims to discuss the structure, function and dynamics of the breast gland and how changes to the function of the breast’s cells can lead to different types of cancer. Abstract The human breast gland is a unique organ as most of its development occurs postnatally between menarche and menopause, a period ranging from 30 to 40 years. During this period, the monthly menstruation cycle drives the mammary gland through phases of cell proliferation, differentiation, and apoptosis, facilitated via a closely choreographed interaction between the epithelial cells and the surrounding stroma preparing the gland for pregnancy. If pregnancy occurs, maximal differentiation is reached to prepare for lactation. After lactation, the mammary gland involutes to a pre-pregnant state. These cycles of proliferation, differentiation, and involution necessitate the presence of epithelial stem cells that give rise to progenitor cells which differentiate further into the luminal and myoepithelial lineages that constitute the epithelial compartment and are responsible for the branching structure of the gland. Maintaining homeostasis and the stem cell niche depends strongly on signaling between the stem and progenitor cells and the surrounding stroma. Breast cancer is a slowly progressing disease whose initiation can take decades to progress into an invasive form. Accumulating evidence indicates that stem cells and/or progenitor cells at different stages, rather than terminally differentiated cells are the main cells of origin for most breast cancer subgroups. Stem cells and cancer cells share several similarities such as increased survival and cellular plasticity which is reflected in their ability to switch fate by receiving intrinsic and extrinsic signals. In this review, we discuss the concept of cellular plasticity in normal breast morphogenesis and cancer, and how the stromal environment plays a vital role in cancer initiation and progression.
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Affiliation(s)
- Saevar Ingthorsson
- Stem Cell Research Unit, Biomedical Center, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland
- Faculty of nursing and midwifery, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland
| | - Gunnhildur Asta Traustadottir
- Stem Cell Research Unit, Biomedical Center, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland
- Department of Pathology, Landspitali University Hospital, 101 Reykjavik, Iceland
| | - Thorarinn Gudjonsson
- Stem Cell Research Unit, Biomedical Center, School of Health Sciences, University of Iceland, 101 Reykjavik, Iceland
- Department of Laboratory Hematology, Landspitali University Hospital, 101 Reykjavik, Iceland
- Correspondence:
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Brown G. Lessons to cancer from studies of leukemia and hematopoiesis. Front Cell Dev Biol 2022; 10:993915. [PMID: 36204679 PMCID: PMC9531023 DOI: 10.3389/fcell.2022.993915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
The starting point to describing the origin and nature of any cancer must be knowledge about how the normal counterpart tissue develops. New principles to the nature of hematopoietic stem cells have arisen in recent years. In particular, hematopoietic stem cells can “choose” a cell lineage directly from a spectrum of the end-cell options, and are, therefore, a heterogeneous population of lineage affiliated/biased cells. These cells remain versatile because the developmental trajectories of hematopoietic stem and progenitor cells are broad. From studies of human acute myeloid leukemia, leukemia is also a hierarchy of maturing or partially maturing cells that are sustained by leukemia stem cells at the apex. This cellular hierarchy model has been extended to a wide variety of human solid tumors, by the identification of cancer stem cells, and is termed the cancer stem cell model. At least, two genomic insults are needed for cancer, as seen from studies of human childhood acute lymphoblastic leukemia. There are signature mutations for some leukemia’s and some relate to a transcription factor that guides the cell lineage of developing hematopoietic stem/progenitor cells. Similarly, some oncogenes restrict the fate of leukemia stem cells and their offspring to a single maturation pathway. In this case, a loss of intrinsic stem cell versatility seems to be a property of leukemia stem cells. To provide more effective cures for leukemia, there is the need to find ways to eliminate leukemia stem cells.
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Martínez-Sifuentes MA, Bassol-Mayagoitia S, Nava-Hernández MP, Ruiz-Flores P, Ramos-Treviño J, Haro-Santa Cruz J, Hernández-Ibarra JA. Survivin in Breast Cancer: A Review. Genet Test Mol Biomarkers 2022; 26:411-421. [PMID: 36166738 DOI: 10.1089/gtmb.2021.0286] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Breast cancer is the most frequently diagnosed cancer in women and ranks second among causes for cancer-related death in women. Gene technology has led to the recognition that breast cancer is a heterogeneous disease composed of different biological subtypes, and genetic profiling enables the response to chemotherapy to be predicted. This fact emphasizes the importance of selecting sensitive diagnostic and prognostic markers in the early disease stage and more efficient targeted treatments for this disease. One such prognostic marker appears to be survivin. Many studies have shown that survivin is strongly expressed in different types of cancers. Its overexpression has been demonstrated in breast cancer, and high activity of the survivin gene has been associated with a poor prognosis and worse survival rates.
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Affiliation(s)
- Manuel Antonio Martínez-Sifuentes
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Susana Bassol-Mayagoitia
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Martha P Nava-Hernández
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Pablo Ruiz-Flores
- Department of Genetics and Molecular Medicine, Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Juan Ramos-Treviño
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - Jorge Haro-Santa Cruz
- Department of Genetics and Molecular Medicine, Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
| | - José Anselmo Hernández-Ibarra
- Department of Reproductive Biology and Biomedical Research Center, School of Medicine, Autonomous University of Coahuila, Torreón, Mexico
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Mahmoud R, Ordóñez-Morán P, Allegrucci C. Challenges for Triple Negative Breast Cancer Treatment: Defeating Heterogeneity and Cancer Stemness. Cancers (Basel) 2022; 14:cancers14174280. [PMID: 36077812 PMCID: PMC9454775 DOI: 10.3390/cancers14174280] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/12/2022] [Accepted: 08/26/2022] [Indexed: 11/25/2022] Open
Abstract
The Triple Negative Breast Cancer (TNBC) subtype is known to have a more aggressive clinical course compared to other breast cancer subtypes. Targeted therapies for this type of breast cancer are limited and patients are mostly treated with conventional chemo- and radio-therapies which are not specific and do not target resistant cells. Therefore, one of the major clinical challenges is to find compounds that target the drug-resistant cell populations which are responsible for reforming secondary tumours. The molecular profiling of the different TNBC subtypes holds a promise for better defining these resistant cells specific to each tumour. To this end, a better understanding of TNBC heterogeneity and cancer stemness is required, and extensive genomic analysis can help to understand the disease complexity and distinguish new molecular drivers that can be targeted in the clinics. The use of persister cancer cell-targeting therapies combined with other therapies may provide a big advance to improve TNBC patients' survival.
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Affiliation(s)
- Rinad Mahmoud
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
| | - Paloma Ordóñez-Morán
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Translational Medical Sciences Unit, School of Medicine, University of Nottingham, Nottingham NG7 2RD, UK
- Correspondence: (P.O.-M.); (C.A.)
| | - Cinzia Allegrucci
- Centre for Cancer Sciences, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- Nottingham Breast Cancer Research Centre, Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK
- SVMS, University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK
- Correspondence: (P.O.-M.); (C.A.)
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da Luz FAC, Araújo BJ, de Araújo RA. The current staging and classification systems of breast cancer and their pitfalls: Is it possible to integrate the complexity of this neoplasm into a unified staging system? Crit Rev Oncol Hematol 2022; 178:103781. [PMID: 35953011 DOI: 10.1016/j.critrevonc.2022.103781] [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: 03/30/2022] [Revised: 06/21/2022] [Accepted: 08/06/2022] [Indexed: 11/29/2022] Open
Abstract
Breast cancer is one of the leading causes of cancer death in women worldwide due to its variable aggressiveness and high propensity to develop distant metastases. The staging can be performed clinically or pathologically, generating the stage stratification by the TNM (T - tumor size; N- lymph node metastasis; M - distant organ metastasis) system. However, cancers with virtually identical TNM characteristics can present highly contrasting behaviors due to the divergence of molecular profiles. This review focuses on the histopathological nuances and molecular understanding of breast cancer through the profiling of gene and protein expression, culminating in improvements promoted by the integration of this information into the traditional staging system. As a culminating point, it will highlight predictive statistical tools for genomic risks and decision algorithms as a possible solution to integrate the various systems because they have the potential to reduce the indications for such tests, serving as a funnel in association with staging and previous classification.
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Affiliation(s)
- Felipe Andrés Cordero da Luz
- Center for Cancer Prevention and Research, Uberlandia Cancer Hospital, Av Amazonas nº 1996, Umuarama, Uberlândia, Minas Gerais, MG 38405-302, Brazil
| | - Breno Jeha Araújo
- São Paulo State Cancer Institute of the Medical School of the University of São Paulo, Av. Dr. Arnaldo 251, São Paulo, São Paulo, SP 01246-000, Brazil
| | - Rogério Agenor de Araújo
- Medical Faculty, Federal University of Uberlandia, Av Pará nº 1720, Bloco 2U, Umuarama, Uberlândia, Minas Gerais, MG 38400-902, Brazil.
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Acevedo-Díaz A, Morales-Cabán BM, Zayas-Santiago A, Martínez-Montemayor MM, Suárez-Arroyo IJ. SCAMP3 Regulates EGFR and Promotes Proliferation and Migration of Triple-Negative Breast Cancer Cells through the Modulation of AKT, ERK, and STAT3 Signaling Pathways. Cancers (Basel) 2022; 14:2807. [PMID: 35681787 PMCID: PMC9179572 DOI: 10.3390/cancers14112807] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Revised: 06/02/2022] [Accepted: 06/03/2022] [Indexed: 12/04/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive, metastatic, and lethal breast cancer subtype. To improve the survival of TNBC patients, it is essential to explore new signaling pathways for the further development of effective drugs. This study aims to investigate the role of the secretory carrier membrane protein 3 (SCAMP3) in TNBC and its association with the epidermal growth factor receptor (EGFR). Through an internalization assay, we demonstrated that SCAMP3 colocalizes and redistributes EGFR from the cytoplasm to the perinucleus. Furthermore, SCAMP3 knockout decreased proliferation, colony and tumorsphere formation, cell migration, and invasion of TNBC cells. Immunoblots and degradation assays showed that SCAMP3 regulates EGFR through its degradation. In addition, SCAMP3 modulates AKT, ERK, and STAT3 signaling pathways. TNBC xenograft models showed that SCAMP3 depletion delayed tumor cell proliferation at the beginning of tumor development and modulated the expression of genes from the PDGF pathway. Additionally, analysis of TCGA data revealed elevated SCAMP3 expression in breast cancer tumors. Finally, patients with TNBC with high expression of SCAMP3 showed decreased RFS and DMFS. Our findings indicate that SCAMP3 could contribute to TNBC development through the regulation of multiple pathways and has the potential to be a target for breast cancer therapy.
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Affiliation(s)
| | - Beatriz M. Morales-Cabán
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, PR 00960, USA; (B.M.M.-C.); (M.M.M.-M.)
| | - Astrid Zayas-Santiago
- Department of Pathology, School of Medicine, Universidad Central del Caribe, Bayamón, PR 00960, USA;
| | - Michelle M. Martínez-Montemayor
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, PR 00960, USA; (B.M.M.-C.); (M.M.M.-M.)
| | - Ivette J. Suárez-Arroyo
- Department of Biochemistry, School of Medicine, Universidad Central del Caribe, Bayamón, PR 00960, USA; (B.M.M.-C.); (M.M.M.-M.)
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Sengupta S, Mondal M, Prasasvi KR, Mukherjee A, Magod P, Urbach S, Friedmann-Morvinski D, Marin P, Somasundaram K. Differentiated glioma cell-derived Fibromodulin activates Integrin-dependent Notch signaling in endothelial cells to promote tumor angiogenesis and growth. eLife 2022; 11:78972. [PMID: 35642785 PMCID: PMC9259034 DOI: 10.7554/elife.78972] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/29/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) alone can initiate and maintain tumors, but the function of non-cancer stem cells (non-CSCs) that form the tumor bulk remains poorly understood. Proteomic analysis showed a higher abundance of the extracellular matrix small leucine-rich proteoglycan fibromodulin (FMOD) in the conditioned medium of differentiated glioma cells (DGCs), the equivalent of glioma non-CSCs, compared to that of glioma stem-like cells (GSCs). DGCs silenced for FMOD fail to cooperate with co-implanted GSCs to promote tumor growth. FMOD downregulation neither affects GSC growth and differentiation nor DGC growth and reprogramming in vitro. DGC-secreted FMOD promotes angiogenesis by activating integrin-dependent Notch signaling in endothelial cells. Furthermore, conditional silencing of FMOD in newly generated DGCs in vivo inhibits the growth of GSC-initiated tumors due to poorly developed vasculature and increases mouse survival. Collectively, these findings demonstrate that DGC-secreted FMOD promotes glioma tumor angiogenesis and growth through paracrine signaling in endothelial cells and identifies a DGC-produced protein as a potential therapeutic target in glioma.
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Affiliation(s)
- Shreoshi Sengupta
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Mainak Mondal
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Kaval Reddy Prasasvi
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Arani Mukherjee
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
| | - Prerna Magod
- School of Neurobiology, Biochemistry and Biophysics, Tel Aviv University, Tel Aviv, Israel
| | - Serge Urbach
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Philippe Marin
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Kumaravel Somasundaram
- Department of Microbiology and Cell Biology, Indian Institute of Science Bangalore, Bangalore, India
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Uprety B, Abrahamse H. Targeting Breast Cancer and Their Stem Cell Population through AMPK Activation: Novel Insights. Cells 2022; 11:576. [PMID: 35159385 PMCID: PMC8834477 DOI: 10.3390/cells11030576] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/24/2022] [Accepted: 01/25/2022] [Indexed: 02/06/2023] Open
Abstract
Despite some significant advancements, breast cancer has become the most prevalent cancer in the world. One of the main reasons for failure in treatment and metastasis has been attributed to the presence of cancer initiating cells-cancer stem cells. Consequently, research is now being focussed on targeting cancer cells along with their stem cell population. Non-oncology drugs are gaining increasing attention for their potent anticancer activities. Metformin, a drug commonly used to treat type 2 diabetes, is the best example in this regard. It exerts its therapeutic action by activating 5' adenosine monophosphate-activated protein kinase (AMPK). Activated AMPK subsequently phosphorylates and targets several cellular pathways involved in cell growth and proliferation and the maintenance of stem-like properties of cancer stem cells. Therefore, AMPK is emerging as a target of choice for developing effective anticancer drugs. Vanadium compounds are well-known PTP inhibitors and AMPK activators. They find extensive applications in treatment of diabetes and obesity via PTP1B inhibition and AMPK-mediated inhibition of adipogenesis. However, their role in targeting cancer stem cells has not been explored yet. This review is an attempt to establish the applications of insulin mimetic vanadium compounds for the treatment of breast cancer by AMPK activation and PTP1B inhibition pathways.
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Affiliation(s)
- Bhawna Uprety
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein 2028, South Africa;
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31
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Wilczyński JR. Cancer Stem Cells: An Ever-Hiding Foe. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:219-251. [PMID: 35165866 DOI: 10.1007/978-3-030-91311-3_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cancer stem cells are a population of cells enable to reproduce the original phenotype of the tumor and capable to self-renewal, which is crucial for tumor proliferation, differentiation, recurrence, and metastasis, as well as chemoresistance. Therefore, the cancer stem cells (CSCs) have become one of the main targets for anticancer therapy and many ongoing clinical trials test anti-CSCs efficacy of plenty of drugs. This chapter describes CSCs starting from general description of this cell population, through CSCs markers, signaling pathways, genetic and epigenetic regulation, role of epithelial-mesenchymal transition (EMT) transition and autophagy, cooperation with microenvironment (CSCs niche), and finally role of CSCs in escaping host immunosurveillance against cancer.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
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Joe NS, Godet I, Milki N, Ain NUI, Oza HH, Riggins GJ, Gilkes DM. Mebendazole prevents distant organ metastases in part by decreasing ITGβ4 expression and cancer stemness. Breast Cancer Res 2022; 24:98. [PMID: 36578038 PMCID: PMC9798635 DOI: 10.1186/s13058-022-01591-3] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 12/09/2022] [Indexed: 12/29/2022] Open
Abstract
Breast cancer is the most diagnosed cancer among women. Approximately 15-20% of all breast cancers are highly invasive triple-negative breast cancer (TNBC) and lack estrogen, progesterone, and ERBB2 receptors. TNBC is challenging to treat due to its aggressive nature with far fewer targeted therapies than other breast cancer subtypes. Current treatments for patients with TNBC consist of cytotoxic chemotherapies, surgery, radiation, and in some instances PARP inhibitors and immunotherapy. To advance current therapeutics, we repurposed mebendazole (MBZ), an orally available FDA-approved anthelmintic that has shown preclinical efficacy for cancers. MBZ has low toxicity in humans and efficacy in multiple cancer models including breast cancer, glioblastoma multiforme, medulloblastoma, colon cancer, pancreatic and thyroid cancer. MBZ was well-tolerated in a phase I clinical trial of adults recently diagnosed with glioma. We determined that the half-maximal inhibitory concentration (IC50) of MBZ in four breast cancer cell lines is well within the range reported for other types of cancer. MBZ reduced TNBC cell proliferation, induced apoptosis, and caused G2/M cell cycle arrest. MBZ reduced the size of primary tumors and prevented lung and liver metastases. In addition, we uncovered a novel mechanism of action for MBZ. We found that MBZ reduces integrin β4 (ITGβ4) expression and cancer stem cell properties. ITGβ4 has previously been implicated in promoting "cancer stemness," which may contribute to the efficacy of MBZ. Collectively, our results contribute to a growing body of evidence suggesting that MBZ should be considered as a therapeutic to slow tumor progression and prevent metastasis.
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Affiliation(s)
- Natalie S. Joe
- grid.21107.350000 0001 2171 9311Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA
| | - Inês Godet
- grid.21107.350000 0001 2171 9311Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218 USA ,grid.21107.350000 0001 2171 9311Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218 USA
| | - Nubaira Milki
- grid.21107.350000 0001 2171 9311Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218 USA
| | - Noor U. I. Ain
- grid.21107.350000 0001 2171 9311NIH NIDDK Short-Term Research Experience Program to Unlock Potential (STEP-UP), The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA
| | - Harsh H. Oza
- grid.21107.350000 0001 2171 9311Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA
| | - Gregory J. Riggins
- grid.21107.350000 0001 2171 9311Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA
| | - Daniele M. Gilkes
- grid.21107.350000 0001 2171 9311Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Cellular and Molecular Medicine Program, The Johns Hopkins University School of Medicine, Baltimore, MD 21231 USA ,grid.21107.350000 0001 2171 9311Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, MD 21218 USA ,grid.21107.350000 0001 2171 9311Johns Hopkins Institute for NanoBioTechnology, The Johns Hopkins University, Baltimore, MD 21218 USA
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SOX2 maintains the stemness of retinoblastoma stem-like cells through Hippo/YAP signaling pathway. Exp Eye Res 2021; 214:108887. [PMID: 34890603 DOI: 10.1016/j.exer.2021.108887] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 11/22/2021] [Accepted: 12/02/2021] [Indexed: 01/08/2023]
Abstract
PURPOSE To explore the mechanisms underlying stemness maintenance of retinoblastoma (RB) stem cells (RSCs). METHODS The retinoblastoma stem-like cells (RSLCs) were isolated by single cell cloning in combination of examination of sphere-forming capacities. The stemness of the cells were characterized by the sphere-forming capacity and the expression levels of RSCs markers. Gene manipulation was performed by lentivirus system. Transcriptional regulation was identified by qRT-PCR, luciferase reporter, nuclear run-on and DNA pull-down assay. Spearman analysis was employed for correlation analysis of genes in tumor tissues of RB patients. RESULTS The isolated RSLCs exhibited enhanced sphere-forming capacity and constantly higher levels of CD44, ABCG2, SOX2 and PAX6, but not CD133. SOX2 positively regulated the stemness of RSLCs. SOX2 directly binds to the promoters of WWTR1 and YAP and transcriptionally activates WWTR1 and YAP. Knockdown of WWTR1 or YAP partially abolished the effect of SOX2 on the stemness of RSLCs. CONCLUSIONS SOX2, as a key deriver, maintains RB stemness by activating Hippo/YAP signaling. Inhibition of Hippo/YAP signaling would be an effective strategy for human RB caused by SOX2 upregulation.
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Nisticò C, Pagliari F, Chiarella E, Fernandes Guerreiro J, Marafioti MG, Aversa I, Genard G, Hanley R, Garcia-Calderón D, Bond HM, Mesuraca M, Tirinato L, Spadea MF, Seco JC. Lipid Droplet Biosynthesis Impairment through DGAT2 Inhibition Sensitizes MCF7 Breast Cancer Cells to Radiation. Int J Mol Sci 2021; 22:10102. [PMID: 34576263 PMCID: PMC8466244 DOI: 10.3390/ijms221810102] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 09/15/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most frequent cancer in women worldwide and late diagnosis often adversely affects the prognosis of the disease. Radiotherapy is commonly used to treat breast cancer, reducing the risk of recurrence after surgery. However, the eradication of radioresistant cancer cells, including cancer stem cells, remains the main challenge of radiotherapy. Recently, lipid droplets (LDs) have been proposed as functional markers of cancer stem cells, also being involved in increased cell tumorigenicity. LD biogenesis is a multistep process requiring various enzymes, including Diacylglycerol acyltransferase 2 (DGAT2). In this context, we evaluated the effect of PF-06424439, a selective DGAT2 inhibitor, on MCF7 breast cancer cells exposed to X-rays. Our results demonstrated that 72 h of PF-06424439 treatment reduced LD content and inhibited cell migration, without affecting cell proliferation. Interestingly, PF-06424439 pre-treatment followed by radiation was able to enhance radiosensitivity of MCF7 cells. In addition, the combined treatment negatively interfered with lipid metabolism-related genes, as well as with EMT gene expression, and modulated the expression of typical markers associated with the CSC-like phenotype. These findings suggest that PF-06424439 pre-treatment coupled to X-ray exposure might potentiate breast cancer cell radiosensitivity and potentially improve the radiotherapy effectiveness.
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Affiliation(s)
- Clelia Nisticò
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Francesca Pagliari
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Emanuela Chiarella
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
| | - Joana Fernandes Guerreiro
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
- Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10 (km 1397), 2695-066 Bobadela LRS, Portugal
| | - Maria Grazia Marafioti
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Ilenia Aversa
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Geraldine Genard
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Rachel Hanley
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
- Department of Physics and Astronomy, Heidelberg University, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany
| | - Daniel Garcia-Calderón
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
- Department of Physics and Astronomy, Heidelberg University, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany
| | - Heather Mandy Bond
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
| | - Maria Mesuraca
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
| | - Luca Tirinato
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
| | - Maria Francesca Spadea
- Department of Clinical and Experimental Medicine, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; (C.N.); (E.C.); (M.G.M.); (I.A.); (H.M.B.); (M.M.)
| | - Joao Carlos Seco
- Division of BioMedical Physics in Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany; (F.P.); (J.F.G.); (G.G.); (R.H.); (D.G.-C.)
- Department of Physics and Astronomy, Heidelberg University, Im Neuenheimer Feld 227, 69120 Heidelberg, Germany
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Neagu AN, Whitham D, Buonanno E, Jenkins A, Alexa-Stratulat T, Tamba BI, Darie CC. Proteomics and its applications in breast cancer. Am J Cancer Res 2021; 11:4006-4049. [PMID: 34659875 PMCID: PMC8493401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 07/05/2021] [Indexed: 06/13/2023] Open
Abstract
Breast cancer is an individually unique, multi-faceted and chameleonic disease, an eternal challenge for the new era of high-integrated precision diagnostic and personalized oncomedicine. Besides traditional single-omics fields (such as genomics, epigenomics, transcriptomics and metabolomics) and multi-omics contributions (proteogenomics, proteotranscriptomics or reproductomics), several new "-omics" approaches and exciting proteomics subfields are contributing to basic and advanced understanding of these "multiple diseases termed breast cancer": phenomics/cellomics, connectomics and interactomics, secretomics, matrisomics, exosomics, angiomics, chaperomics and epichaperomics, phosphoproteomics, ubiquitinomics, metalloproteomics, terminomics, degradomics and metadegradomics, adhesomics, stressomics, microbiomics, immunomics, salivaomics, materiomics and other biomics. Throughout the extremely complex neoplastic process, a Breast Cancer Cell Continuum Concept (BCCCC) has been modeled in this review as a spatio-temporal and holistic approach, as long as the breast cancer represents a complex cascade comprising successively integrated populations of heterogeneous tumor and cancer-associated cells, that reflect the carcinoma's progression from a "driving mutation" and formation of the breast primary tumor, toward the distant secondary tumors in different tissues and organs, via circulating tumor cell populations. This BCCCC is widely sustained by a Breast Cancer Proteomic Continuum Concept (BCPCC), where each phenotype of neoplastic and tumor-associated cells is characterized by a changing and adaptive proteomic profile detected in solid and liquid minimal invasive biopsies by complex proteomics approaches. Such a profile is created, beginning with the proteomic landscape of different neoplastic cell populations and cancer-associated cells, followed by subsequent analysis of protein biomarkers involved in epithelial-mesenchymal transition and intravasation, circulating tumor cell proteomics, and, finally, by protein biomarkers that highlight the extravasation and distant metastatic invasion. Proteomics technologies are producing important data in breast cancer diagnostic, prognostic, and predictive biomarkers discovery and validation, are detecting genetic aberrations at the proteome level, describing functional and regulatory pathways and emphasizing specific protein and peptide profiles in human tissues, biological fluids, cell lines and animal models. Also, proteomics can identify different breast cancer subtypes and specific protein and proteoform expression, can assess the efficacy of cancer therapies at cellular and tissular level and can even identify new therapeutic target proteins in clinical studies.
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Affiliation(s)
- Anca-Narcisa Neagu
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of IașiCarol I bvd. No. 22, Iași 700505, Romania
| | - Danielle Whitham
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Emma Buonanno
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Avalon Jenkins
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Teodora Alexa-Stratulat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and PharmacyIndependenței bvd. No. 16-18, Iași 700021, Romania
| | - Bogdan Ionel Tamba
- Advanced Center for Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and PharmacyMihail Kogălniceanu Street No. 9-13, Iași 700454, Romania
| | - Costel C Darie
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
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Miyano M, Sayaman RW, Shalabi SF, Senapati P, Lopez JC, Angarola BL, Hinz S, Zirbes A, Anczukow O, Yee LD, Sedrak MS, Stampfer MR, Seewaldt VL, LaBarge MA. Breast-Specific Molecular Clocks Comprised of ELF5 Expression and Promoter Methylation Identify Individuals Susceptible to Cancer Initiation. Cancer Prev Res (Phila) 2021; 14:779-794. [PMID: 34140348 PMCID: PMC8338914 DOI: 10.1158/1940-6207.capr-20-0635] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 04/29/2021] [Accepted: 06/07/2021] [Indexed: 01/09/2023]
Abstract
A robust breast cancer prevention strategy requires risk assessment biomarkers for early detection. We show that expression of ELF5, a transcription factor critical for normal mammary development, is downregulated in mammary luminal epithelia with age. DNA methylation of the ELF5 promoter is negatively correlated with expression in an age-dependent manner. Both ELF5 methylation and gene expression were used to build biological clocks to estimate chronological ages of mammary epithelia. ELF5 clock-based estimates of biological age in luminal epithelia from average-risk women were within three years of chronological age. Biological ages of breast epithelia from BRCA1 or BRCA2 mutation carriers, who were high risk for developing breast cancer, suggested they were accelerated by two decades relative to chronological age. The ELF5 DNA methylation clock had better performance at predicting biological age in luminal epithelial cells as compared with two other epigenetic clocks based on whole tissues. We propose that the changes in ELF5 expression or ELF5-proximal DNA methylation in luminal epithelia are emergent properties of at-risk breast tissue and constitute breast-specific biological clocks. PREVENTION RELEVANCE: ELF5 expression or DNA methylation level at the ELF5 promoter region can be used as breast-specific biological clocks to identify women at higher than average risk of breast cancer.
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Affiliation(s)
- Masaru Miyano
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
| | - Rosalyn W Sayaman
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
- Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California
| | - Sundus F Shalabi
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, California
| | - Parijat Senapati
- Department of Diabetes Complications and Metabolism, Beckman Research Institute at City of Hope, Duarte, California
| | - Jennifer C Lopez
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
| | | | - Stefan Hinz
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
| | - Arrianna Zirbes
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
- Irell and Manella Graduate School of Biological Sciences, City of Hope, Duarte, California
| | - Olga Anczukow
- The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut
| | - Lisa D Yee
- Department of Surgery, City of Hope National Medical Center, Duarte, California
| | - Mina S Sedrak
- Center for Cancer and Aging, City of Hope, Duarte, California
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, California
| | - Martha R Stampfer
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California
| | - Victoria L Seewaldt
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California
| | - Mark A LaBarge
- Department of Population Sciences, Beckman Research Institute at City of Hope, Duarte, California.
- Center for Cancer and Aging, City of Hope, Duarte, California
- Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, California
- Center for Cancer Biomarkers, University of Bergen, Bergen, Norway
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Ghaderi F, Jokar N, Gholamrezanezhad A, Assadi M, Ahmadzadehfar H. Toward radiotheranostics in cancer stem cells: a promising initial step for tumour eradication. Clin Transl Imaging 2021. [DOI: 10.1007/s40336-021-00444-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Niklaus NJ, Tokarchuk I, Zbinden M, Schläfli AM, Maycotte P, Tschan MP. The Multifaceted Functions of Autophagy in Breast Cancer Development and Treatment. Cells 2021; 10:cells10061447. [PMID: 34207792 PMCID: PMC8229352 DOI: 10.3390/cells10061447] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/04/2021] [Accepted: 06/04/2021] [Indexed: 12/12/2022] Open
Abstract
Macroautophagy (herein referred to as autophagy) is a complex catabolic process characterized by the formation of double-membrane vesicles called autophagosomes. During this process, autophagosomes engulf and deliver their intracellular content to lysosomes, where they are degraded by hydrolytic enzymes. Thereby, autophagy provides energy and building blocks to maintain cellular homeostasis and represents a dynamic recycling mechanism. Importantly, the clearance of damaged organelles and aggregated molecules by autophagy in normal cells contributes to cancer prevention. Therefore, the dysfunction of autophagy has a major impact on the cell fate and can contribute to tumorigenesis. Breast cancer is the most common cancer in women and has the highest mortality rate among all cancers in women worldwide. Breast cancer patients often have a good short-term prognosis, but long-term survivors often experience aggressive recurrence. This phenomenon might be explained by the high heterogeneity of breast cancer tumors rendering mammary tumors difficult to target. This review focuses on the mechanisms of autophagy during breast carcinogenesis and sheds light on the role of autophagy in the traits of aggressive breast cancer cells such as migration, invasion, and therapeutic resistance.
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Affiliation(s)
- Nicolas J. Niklaus
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Igor Tokarchuk
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
| | - Mara Zbinden
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Anna M. Schläfli
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
| | - Paola Maycotte
- Centro de Investigación Biomédica de Oriente (CIBIOR), Instituto Mexicano del Seguro Social (IMSS), Puebla 74360, Mexico;
| | - Mario P. Tschan
- Institute of Pathology, University of Bern, CH-3008 Bern, Switzerland; (N.J.N.); (I.T.); (M.Z.); (A.M.S.)
- Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3012 Bern, Switzerland
- Correspondence: ; Tel.: +41-31-632-87-80
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Saeki K, Chang G, Kanaya N, Wu X, Wang J, Bernal L, Ha D, Neuhausen SL, Chen S. Mammary cell gene expression atlas links epithelial cell remodeling events to breast carcinogenesis. Commun Biol 2021; 4:660. [PMID: 34079055 PMCID: PMC8172904 DOI: 10.1038/s42003-021-02201-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 05/11/2021] [Indexed: 01/01/2023] Open
Abstract
The female mammary epithelium undergoes reorganization during development, pregnancy, and menopause, linking higher risk with breast cancer development. To characterize these periods of complex remodeling, here we report integrated 50 K mouse and 24 K human mammary epithelial cell atlases obtained by single-cell RNA sequencing, which covers most lifetime stages. Our results indicate a putative trajectory that originates from embryonic mammary stem cells which differentiates into three epithelial lineages (basal, luminal hormone-sensing, and luminal alveolar), presumably arising from unipotent progenitors in postnatal glands. The lineage-specific genes infer cells of origin of breast cancer using The Cancer Genome Atlas data and single-cell RNA sequencing of human breast cancer, as well as the association of gland reorganization to different breast cancer subtypes. This comprehensive mammary cell gene expression atlas ( https://mouse-mammary-epithelium-integrated.cells.ucsc.edu ) presents insights into the impact of the internal and external stimuli on the mammary epithelium at an advanced resolution.
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Affiliation(s)
- Kohei Saeki
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Gregory Chang
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Noriko Kanaya
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Xiwei Wu
- Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Jinhui Wang
- Integrative Genomics Core, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Lauren Bernal
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Desiree Ha
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Susan L Neuhausen
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
| | - Shiuan Chen
- Department of Cancer Biology, Beckman Research Institute of City of Hope, Duarte, CA, USA.
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40
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Wang X, Wang C, Guan J, Chen B, Xu L, Chen C. Progress of Breast Cancer basic research in China. Int J Biol Sci 2021; 17:2069-2079. [PMID: 34131406 PMCID: PMC8193257 DOI: 10.7150/ijbs.60631] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.
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Affiliation(s)
- Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Chao Wang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Jiaheng Guan
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lin Xu
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue. Int J Mol Sci 2021; 22:ijms22094673. [PMID: 33925129 PMCID: PMC8125767 DOI: 10.3390/ijms22094673] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Breast cancer, specifically metastatic breast, is a leading cause of morbidity and mortality in women. This is mainly due to relapse and reoccurrence of tumor. The primary reason for cancer relapse is the development of multidrug resistance (MDR) hampering the treatment and prognosis. MDR can occur due to a multitude of molecular events, including increased expression of efflux transporters such as P-gp, BCRP, or MRP1; epithelial to mesenchymal transition; and resistance development in breast cancer stem cells. Excessive dose dumping in chemotherapy can cause intrinsic anti-cancer MDR to appear prior to chemotherapy and after the treatment. Hence, novel targeted nanomedicines encapsulating chemotherapeutics and gene therapy products may assist to overcome cancer drug resistance. Targeted nanomedicines offer innovative strategies to overcome the limitations of conventional chemotherapy while permitting enhanced selectivity to cancer cells. Targeted nanotheranostics permit targeted drug release, precise breast cancer diagnosis, and importantly, the ability to overcome MDR. The article discusses various nanomedicines designed to selectively target breast cancer, triple negative breast cancer, and breast cancer stem cells. In addition, the review discusses recent approaches, including combination nanoparticles (NPs), theranostic NPs, and stimuli sensitive or “smart” NPs. Recent innovations in microRNA NPs and personalized medicine NPs are also discussed. Future perspective research for complex targeted and multi-stage responsive nanomedicines for metastatic breast cancer is discussed.
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Song K, Farzaneh M. Signaling pathways governing breast cancer stem cells behavior. Stem Cell Res Ther 2021; 12:245. [PMID: 33863385 PMCID: PMC8052733 DOI: 10.1186/s13287-021-02321-w] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the second common cancer and the leading cause of malignancy among females overall. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that play a critical role in the metastasis of breast cancer to other organs in the body. BCSCs have both self-renewal and differentiation capacities, which are thought to contribute to the aggressiveness of metastatic lesions. Therefore, targeting BCSCs can be a suitable approach for the treatment and metastasis of breast cancer. Growing evidence has indicated that the Wnt, NFκB, Notch, BMP2, STAT3, and hedgehog (Hh) signaling pathways govern epithelial-to-mesenchymal transition (EMT) activation, growth, and tumorigenesis of BCSCs in the primary regions. miRNAs as the central regulatory molecules also play critical roles in BCSC self-renewal, metastasis, and drug resistance. Hence, targeting these pathways might be a novel therapeutic approach for breast cancer diagnosis and therapy. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.
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Affiliation(s)
- Kai Song
- Xuzhou Vocational College of Bioengineering, Xuzhou, 221006, Jiangsu, China.
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Humphries B, Wang Z, Yang C. MicroRNA Regulation of Breast Cancer Stemness. Int J Mol Sci 2021; 22:3756. [PMID: 33916548 PMCID: PMC8038508 DOI: 10.3390/ijms22073756] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 12/22/2022] Open
Abstract
Recent advances in our understanding of breast cancer have demonstrated that cancer stem-like cells (CSCs, also known as tumor-initiating cell (TICs)) are central for progression and recurrence. CSCs are a small subpopulation of cells present in breast tumors that contribute to growth, metastasis, therapy resistance, and recurrence, leading to poor clinical outcome. Data have shown that cancer cells can gain characteristics of CSCs, or stemness, through alterations in key signaling pathways. The dysregulation of miRNA expression and signaling have been well-documented in cancer, and recent studies have shown that miRNAs are associated with breast cancer initiation, progression, and recurrence through regulating CSC characteristics. More specifically, miRNAs directly target central signaling nodes within pathways that can drive the formation, maintenance, and even inhibition of the CSC population. This review aims to summarize these research findings specifically in the context of breast cancer. This review also discusses miRNAs as biomarkers and promising clinical therapeutics, and presents a comprehensive summary of currently validated targets involved in CSC-specific signaling pathways in breast cancer.
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Affiliation(s)
- Brock Humphries
- Center for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109, USA
| | - Zhishan Wang
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109, USA;
| | - Chengfeng Yang
- Division of Cancer Biology, Department of Medicine, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109, USA;
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Kim R, Kin T. Reconsidering the Meaning of Curing Primary Breast Cancer as a Systemic Disease. Front Oncol 2021; 11:639420. [PMID: 33816282 PMCID: PMC8012902 DOI: 10.3389/fonc.2021.639420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 02/22/2021] [Indexed: 11/13/2022] Open
Affiliation(s)
- Ryungsa Kim
- Department of Breast Surgery, Hiroshima Mark Clinic, Hiroshima, Japan
| | - Takanori Kin
- Department of Breast Surgery, Hiroshima City Hospital, Hiroshima, Japan
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Abstract
Accumulating evidence strongly indicates that the presence of cancer stem cells (CSCs) leads to the emergence of worse clinical scenarios, such as chemo- and radiotherapy resistance, metastasis, and cancer recurrence. CSCs are a highly tumorigenic population characterized by self-renewal capacity and differentiation potential. Thus, CSCs establish a hierarchical intratumor organization that enables tumor adaptation to evade the immune response and resist anticancer therapy. YY1 functions as a transcription factor, RNA-binding protein, and 3D chromatin regulator. Thus, YY1 has multiple effects and regulates several molecular processes. Emerging evidence indicates that the development of lethal YY1-mediated cancer phenotypes is associated with the presence of or enrichment in cancer stem-like cells. Therefore, it is necessary to investigate whether and to what extent YY1 regulates the CSC phenotype. Since CSCs mirror the phenotypic behavior of stem cells, we initially describe the roles played by YY1 in embryonic and adult stem cells. Next, we scrutinize evidence supporting the contributions of YY1 in CSCs from a number of various cancer types. Finally, we identify new areas for further investigation into the YY1-CSCs axis, including the participation of YY1 in the CSC niche.
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Kim R, Kin T. Clinical Perspectives in Addressing Unsolved Issues in (Neo)Adjuvant Therapy for Primary Breast Cancer. Cancers (Basel) 2021; 13:926. [PMID: 33672204 PMCID: PMC7927115 DOI: 10.3390/cancers13040926] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 02/18/2021] [Accepted: 02/21/2021] [Indexed: 01/13/2023] Open
Abstract
The treatment of primary breast cancer has evolved over the past 50 years based on the concept that breast cancer is a systemic disease, with the escalation of adjuvant and neoadjuvant therapies and de-escalation of breast cancer surgery. Despite the development of these therapies, recurrence with distant metastasis during the 10 years after surgical treatment is observed, albeit infrequently. Recent advances in genomic analysis based on circulating tumor cells and circulating tumor DNA have enabled the development of targeted therapies based on genetic mutations in residual tumor cells. A paradigm shift involving the application of neoadjuvant chemotherapy (NAC) has enabled the prediction of treatment response and long-term prognoses; additional adjuvant chemotherapy targeting remaining tumor cells after NAC improves survival. The activation of antitumor immunity by anticancer agents may be involved in the eradication of residual tumor cells. Elucidation of the manner in which antitumor immunity is induced by anticancer agents and unknown factors, and the overcoming of drug resistance via the targeted eradication of residual tumor cells based on genomic profiles, will inevitably lead to the achievement of 0% distant recurrence and a complete cure for primary breast cancer.
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Affiliation(s)
- Ryungsa Kim
- Breast Surgery, Hiroshima Mark Clinic, 1-4-3F, 2-Chome, Ohte-machi, Naka-ku, Hiroshima 730-0051, Japan
| | - Takanori Kin
- Department of Breast Surgery, Hiroshima City Hospital, 7-33, Moto-machi, Naka-ku, Hiroshima 730-8518, Japan;
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Lv L, Shi Y, Wu J, Li G. Nanosized Drug Delivery Systems for Breast Cancer Stem Cell Targeting. Int J Nanomedicine 2021; 16:1487-1508. [PMID: 33654398 PMCID: PMC7914063 DOI: 10.2147/ijn.s282110] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/10/2021] [Indexed: 01/15/2023] Open
Abstract
Breast cancer stem cells (BCSCs), also known as breast cancer initiating cells, are reported to be responsible for the initiation, progression, therapeutic resistance, and relapse of breast cancer. Conventional therapeutic agents mainly kill the bulk of breast tumor cells and fail to eliminate BCSCs, even enhancing the fraction of BCSCs in breast tumors sometimes. Therefore, it is essential to develop specific and effective methods of eliminating BCSCs that will enhance the efficacy of killing breast tumor cells and thereby, increase the survival rates and quality of life of breast cancer patients. Despite the availability of an increasing number of anti-BCSC agents, their clinical translations are hindered by many issues, such as instability, low bioavailability, and off-target effects. Nanosized drug delivery systems (NDDSs) have the potential to overcome the drawbacks of anti-BCSC agents by providing site-specific delivery and enhancing of the stability and bioavailability of the delivered agents. In this review, we first briefly introduce the strategies and agents used against BCSCs and then highlight the mechanism of action and therapeutic efficacy of several state-of-the-art NDDSs that can be used to treat breast cancer by eliminating BCSCs.
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Affiliation(s)
- Li Lv
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Yonghui Shi
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China.,Department of Pharmacy, Zengcheng District People's Hospital of Guangzhou, Guangzhou, 511300, Guangdong, People's Republic of China
| | - Junyan Wu
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
| | - Guocheng Li
- Department of Pharmacy, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China.,Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, Guangdong, People's Republic of China
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The Tumor Microenvironment as a Driving Force of Breast Cancer Stem Cell Plasticity. Cancers (Basel) 2020; 12:cancers12123863. [PMID: 33371274 PMCID: PMC7766255 DOI: 10.3390/cancers12123863] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Breast cancer stem cells are a subset of transformed cells that sustain tumor growth and can metastasize to secondary organs. Since metastasis accounts for most cancer deaths, it is of paramount importance to understand the cellular and molecular mechanisms that regulate this subgroup of cells. The tumor microenvironment (TME) is the habitat in which transformed cells evolve, and it is composed by many different cell types and the extracellular matrix (ECM). A body of evidence strongly indicates that microenvironmental cues modulate stemness in breast cancer, and that the coevolution of the TME and cancer stem cells determine the fate of breast tumors. In this review, we summarize the studies providing links between the TME and the breast cancer stem cell phenotype and we discuss their specific interactions with immune cell subsets, stromal cells, and the ECM. Abstract Tumor progression involves the co-evolution of transformed cells and the milieu in which they live and expand. Breast cancer stem cells (BCSCs) are a specialized subset of cells that sustain tumor growth and drive metastatic colonization. However, the cellular hierarchy in breast tumors is rather plastic, and the capacity to transition from one cell state to another depends not only on the intrinsic properties of transformed cells, but also on the interplay with their niches. It has become evident that the tumor microenvironment (TME) is a major player in regulating the BCSC phenotype and metastasis. The complexity of the TME is reflected in its number of players and in the interactions that they establish with each other. Multiple types of immune cells, stromal cells, and the extracellular matrix (ECM) form an intricate communication network with cancer cells, exert a highly selective pressure on the tumor, and provide supportive niches for BCSC expansion. A better understanding of the mechanisms regulating these interactions is crucial to develop strategies aimed at interfering with key BCSC niche factors, which may help reducing tumor heterogeneity and impair metastasis.
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Zhang X, Powell K, Li L. Breast Cancer Stem Cells: Biomarkers, Identification and Isolation Methods, Regulating Mechanisms, Cellular Origin, and Beyond. Cancers (Basel) 2020; 12:E3765. [PMID: 33327542 PMCID: PMC7765014 DOI: 10.3390/cancers12123765] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Despite recent advances in diagnosis and treatment, breast cancer (BC) is still a major cause of cancer-related mortality in women. Breast cancer stem cells (BCSCs) are a small but significant subpopulation of heterogeneous breast cancer cells demonstrating strong self-renewal and proliferation properties. Accumulating evidence has proved that BCSCs are the driving force behind BC tumor initiation, progression, metastasis, drug resistance, and recurrence. As a heterogeneous disease, BC contains a full spectrum of different BC subtypes, and different subtypes of BC further exhibit distinct subtypes and proportions of BCSCs, which correspond to different treatment responses and disease-specific outcomes. This review summarized the current knowledge of BCSC biomarkers and their clinical relevance, the methods for the identification and isolation of BCSCs, and the mechanisms regulating BCSCs. We also discussed the cellular origin of BCSCs and the current advances in single-cell lineage tracing and transcriptomics and their potential in identifying the origin and lineage development of BCSCs.
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Affiliation(s)
- Xiaoli Zhang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
| | | | - Lang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
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Gao X, Dong QZ. Advance in metabolism and target therapy in breast cancer stem cells. World J Stem Cells 2020; 12:1295-1306. [PMID: 33312399 PMCID: PMC7705469 DOI: 10.4252/wjsc.v12.i11.1295] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 09/06/2020] [Accepted: 09/27/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer, like many other cancers, is believed to be driven by a population of cells that display stem cell properties. Recent studies suggest that cancer stem cells (CSCs) are essential for tumor progression, and tumor relapse is thought to be caused by the presence of these cells. CSC-targeted therapies have also been proposed to overcome therapeutic resistance in breast cancer after the traditional therapies. Additionally, the metabolic properties of cancer cells differ markedly from those of normal cells. The efficacy of metabolic targeted therapy has been shown to enhance anti-cancer treatment or overcome therapeutic resistance of breast cancer cells. Metabolic targeting of breast CSCs (BCSCs) may be a very effective strategy for anti-cancer treatment of breast cancer cells. Thus, in this review, we focus on discussing the studies involving metabolism and targeted therapy in BCSCs.
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Affiliation(s)
- Xu Gao
- Department of Breast Surgery, Yiwu Maternity and Children Hospital, Yiwu 322000, Zhejiang Province, China.
| | - Qiong-Zhu Dong
- Department of General Surgery, Cancer Metastasis Institute, Institutes of Biomedical Sciences, Huashan Hospital, Fudan University, Shanghai 200032, China
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