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Yan S, Ji J, Zhang Z, Imam M, Chen H, Zhang D, Wang J. Targeting the crosstalk between estrogen receptors and membrane growth factor receptors in breast cancer treatment: Advances and opportunities. Biomed Pharmacother 2024; 175:116615. [PMID: 38663101 DOI: 10.1016/j.biopha.2024.116615] [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: 01/10/2024] [Revised: 04/06/2024] [Accepted: 04/17/2024] [Indexed: 06/03/2024] Open
Abstract
Estrogens play a critical role in the initiation and progression of breast cancer. Estrogen receptor (ER)α, ERβ, and G protein-coupled estrogen receptor are the primary receptors for estrogen in breast cancer. These receptors are mainly activated by binding with estrogens. The crosstalk between ERs and membrane growth factor receptors creates additional pathways that amplify the effects of their ligands and promote tumor growth. This crosstalk may cause endocrine therapy resistance in ERα-positive breast cancer. Furthermore, this may explain the resistance to anti-human epidermal growth factor receptor-2 (HER2) treatment in ERα-/HER2-positive breast cancer and chemotherapy resistance in triple-negative breast cancer. Accordingly, it is necessary to understand the complex crosstalk between ERs and growth factor receptors. In this review, we delineate the crosstalk between ERs and membrane growth factor receptors in breast cancer. Moreover, this review highlights the current progress in clinical treatment and discusses how pharmaceuticals target the crosstalk. Lastly, we discuss the current challenges and propose potential solutions regarding the implications of targeting crosstalk via pharmacological inhibition. Overall, the present review provides a landscape of the crosstalk between ERs and membrane growth factor receptors in breast cancer, along with valuable insights for future studies and clinical treatments using a chemotherapy-sparing regimen to improve patient quality of life.
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Affiliation(s)
- Shunchao Yan
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China.
| | - Jiale Ji
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Zhijie Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Murshid Imam
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Hong Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Duo Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
| | - Jinpeng Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110022, China
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Wang D, Yang Y, Yang L, Yang H. Bibliometric analysis and visualization of endocrine therapy for breast cancer research in the last two decade. Front Endocrinol (Lausanne) 2023; 14:1287101. [PMID: 38116321 PMCID: PMC10728495 DOI: 10.3389/fendo.2023.1287101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 11/21/2023] [Indexed: 12/21/2023] Open
Abstract
Background Breast cancer endocrine therapy research has become a crucial domain in oncology since hormone receptor-positive breast cancers have been increasingly recognized, and targeted therapeutic interventions have been advancing over the past few years. This bibliometric analysis attempts to shed light on the trends, dynamics, and knowledge hotspots that have shaped the landscape of breast cancer endocrine therapy research between 2003 and 2022. Methods In this study, we comprehensively reviewed the scientific literature spanning the above-mentioned period, which included publications accessible through the database of the Web of Science (WOS) and the National Center for Biotechnology Information (NCBI). Next, a systematic and data-driven analysis supported by sophisticated software tools was conducted, such that the core themes, prolific authors, influential journals, prominent countries, and critical citation patterns in the relevant research field can be clarified. Results A continuous and substantial expansion of breast cancer endocrine therapy research was revealed over the evaluated period. A total of 1,317 scholarly articles were examined. The results of the analysis suggested that research on endocrine therapy for breast cancer has laid a solid basis for the treatment of hormone receptor-positive breast cancer. From a geographical perspective, the US, the UK, and China emerged as the most active contributors, illustrating the global impact of this study. Furthermore, our analysis delineated prominent research topics that have dominated the discourse in the past two decades, including drug therapy, therapeutic efficacy, molecular biomarkers, and hormonal receptor interactions. Conclusion This comprehensive bibliometric analysis provides a panoramic view of the ever-evolving landscape of breast cancer endocrine therapy research. The findings highlight the trajectory of past developments while signifying an avenue of vast opportunities for future investigations and therapeutic advancements. As the field continues to burgeon, this analysis will provide valuable guidance for to researchers toward pertinent knowledge hotspots and emerging trends, which can expedite the discoveries in the realm of breast cancer endocrine therapy.
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Affiliation(s)
| | | | | | - Hongwei Yang
- Department of Breast and Thyroid Surgery, Suining Central Hospital, Suining, Sichuan, China
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3
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Wang Z, Zhang N, Zhang M, Jiang Y, Ng AS, Bridges E, Zhang W, Zeng X, Luo Q, Liang J, Győrffy B, Hublitz P, Liang Z, Fischer R, Kerr D, Harris AL, Cai S. GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner. Cancer Res 2023; 83:3400-3413. [PMID: 37463466 DOI: 10.1158/0008-5472.can-22-3471] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 04/27/2023] [Accepted: 07/14/2023] [Indexed: 07/20/2023]
Abstract
GTP cyclohydrolase (GCH1) is the rate-limiting enzyme for tetrahydrobiopterin (BH4) biosynthesis. The catalysis of BH4 biosynthesis is tightly regulated for physiological neurotransmission, inflammation, and vascular tone. Paradoxically, BH4 has emerged as an oncometabolite regulating tumor growth, but the effects on tumor development remain controversial. Here, we found that GCH1 potentiated the growth of triple-negative breast cancer (TNBC) and HER2+ breast cancer and transformed nontumor breast epithelial cells. Independent of BH4 production, GCH1 protein induced epithelial-to-mesenchymal transition by binding to vimentin (Vim), which was mediated by HSP90. Conversely, GCH1 ablation impaired tumor growth, suppressed Vim in TNBC, and inhibited EGFR/ERK signaling while activating the p53 pathway in estrogen receptor-positive tumor cells. GCH1 deficiency increases tumor cell sensitivity to HSP90 inhibition and endocrine treatments. In addition, high GCH1 correlated with poor breast cancer survival. Together, this study reveals an enzyme-independent oncogenic role of GCH1, presenting it as a potential target for therapeutic development. SIGNIFICANCE GTP cyclohydrolase functions as an oncogene in breast cancer and binds vimentin to induce epithelial-to-mesenchymal transition independently of its enzyme activity, which confers targetable vulnerabilities for developing breast cancer treatment strategies.
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Affiliation(s)
- Zijing Wang
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
- Sichuan University-Oxford University Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Nan Zhang
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
- Sichuan University-Oxford University Huaxi Joint Centre for Gastrointestinal Cancer, West China Hospital, Sichuan University, Chengdu, China
| | - Miao Zhang
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
- School of Acupuncture and Moxibustion, Fujian University of Traditional Chinese Medicine, China
| | - Yao Jiang
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Aik Seng Ng
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Esther Bridges
- Molecular Oncology Laboratories, University Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Wei Zhang
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Xin Zeng
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Qi Luo
- Xiamen Cancer Hospital, Xiamen First Hospital, Xiamen University, Fujian, China
| | - Jiabien Liang
- Xiamen Cancer Hospital, Xiamen First Hospital, Xiamen University, Fujian, China
| | - Balázs Győrffy
- TTK Cancer Biomarker Research Group, Institute of Enzymology, and Semmelweis University Department Bioinformatics and Department of Paediatrics, Budapest, Hungary
| | - Philip Hublitz
- Genome Engineering Facility, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Zhu Liang
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, United Kingdom
| | - Roman Fischer
- Nuffield Department of Medicine, Target Discovery Institute, University of Oxford, Roosevelt Drive, Oxford, United Kingdom
| | - David Kerr
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Adrian L Harris
- Molecular Oncology Laboratories, University Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Shijie Cai
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
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Taurin S, Rosengren RJ. Raloxifene potentiates the effect of gefitinib in triple-negative breast cancer cell lines. Med Oncol 2022; 40:45. [PMID: 36494506 DOI: 10.1007/s12032-022-01909-3] [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: 09/13/2022] [Accepted: 11/22/2022] [Indexed: 06/17/2023]
Abstract
Triple-negative breast cancers (TNBCs) are characterized by a lack of approved targeted therapies and remain a challenge in the clinic. Several overexpressed proteins, including epidermal growth factor receptor (EGFR), have been associated with TNBCs and are considered potential therapeutic targets. However, EGFR inhibitors alone failed to demonstrate a cutting-edge advantage for treating TNBCs over conventional chemotherapies. Studies have shown that selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene also affect TNBC cell viability. The combination of gefitinib and raloxifene was assessed against TNBC cell lines in vitro. Two TNBC cell lines, MDA-MB-231 and MDA-MB-468, were used to investigate the combination of gefitinib and raloxifene on cell viability, DNA synthesis, and apoptosis. The combination was assessed on intracellular signaling pathways, colony formation, migration, and angiogenesis. In the present study, raloxifene, in combination with gefitinib, decreased cell viability. The combination potentiates apoptosis and affects the expression and phosphorylation pattern of proteins involved in cell proliferation, such as NFκB, β-catenin, and EGFR. Furthermore, evidence of apoptosis activation was also observed, along with a decreased cell migration and tumorigenicity of TNBC cells. Moreover, the combined treatment decreased the ability of neovascularization as assessed by tube formation of endothelial cells. These results suggested the potential of the combination of raloxifene and gefitinib for the prevention of TNBC growth and the appearance of metastatic events. Our findings provide the basis for future studies on the mechanism involved in raloxifene-gefitinib inhibition of ER-negative tumor growth.
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Affiliation(s)
- Sebastien Taurin
- Department of Molecular Medicine, College of Medicine and Medical Sciences, Arabian Gulf University, Building 293, Road 2904 Block 329, Manama, 007, Kingdom of Bahrain.
| | - Rhonda J Rosengren
- Department of Pharmacology and Toxicology, University of Otago, Dunedin, New Zealand
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Drago JZ, Ferraro E, Abuhadra N, Modi S. Beyond HER2: Targeting the ErbB receptor family in breast cancer. Cancer Treat Rev 2022; 109:102436. [PMID: 35870237 PMCID: PMC10478787 DOI: 10.1016/j.ctrv.2022.102436] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 07/07/2022] [Accepted: 07/10/2022] [Indexed: 11/28/2022]
Abstract
Targeting the HER2 oncogene represents one of the greatest advances in the treatment of breast cancer. HER2 is one member of the ERBB-receptor family, which includes EGFR (HER1), HER3 and HER4. In the presence or absence of underling genomic aberrations such as mutations or amplification events, intricate interactions between these proteins on the cell membrane lead to downstream signaling that encourages cancer growth and proliferation. In this Review, we contextualize efforts to pharmacologically target the ErbB receptor family beyond HER2, with a focus on EGFR and HER3. Preclinical and clinical efforts are synthesized. We discuss successes and failures of this approach to date, summarize lessons learned, and propose a way forward that invokes new therapeutic modalities such as antibody drug conjugates (ADCs), combination strategies, and patient selection through rational biomarkers.
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Affiliation(s)
- Joshua Z Drago
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weil Cornell Medicine, New York, NY, USA.
| | - Emanuela Ferraro
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nour Abuhadra
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weil Cornell Medicine, New York, NY, USA
| | - Shanu Modi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weil Cornell Medicine, New York, NY, USA
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A kinase inhibitor screen reveals MEK1/2 as a novel therapeutic target to antagonize IGF1R-mediated antiestrogen resistance in ERα-positive luminal breast cancer. Biochem Pharmacol 2022; 204:115233. [PMID: 36041543 DOI: 10.1016/j.bcp.2022.115233] [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: 06/10/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/23/2022]
Abstract
Antiestrogen resistance of breast cancer has been related to enhanced growth factor receptor expression and activation. We have previously shown that ectopic expression and subsequent activation of the insulin-like growth factor-1 receptor (IGF1R) or the epidermal growth factor receptor (EGFR) in MCF7 or T47D breast cancer cells results in antiestrogen resistance. In order to identify novel therapeutic targets to prevent this antiestrogen resistance, we performed kinase inhibitor screens with 273 different inhibitors in MCF7 cells overexpressing IGF1R or EGFR. Kinase inhibitors that antagonized antiestrogen resistance but are not directly involved in IGF1R or EGFR signaling were prioritized for further analyses. Various ALK (anaplastic lymphoma receptor tyrosine kinase) inhibitors inhibited cell proliferation in IGF1R expressing cells under normal and antiestrogen resistance conditions by preventing IGF1R activation and subsequent downstream signaling; the ALK inhibitors did not affect EGFR signaling. On the other hand, MEK (mitogen-activated protein kinase kinase)1/2 inhibitors, including PD0325901, selumetinib, trametinib and TAK733, selectively antagonized IGF1R signaling-mediated antiestrogen resistance but did not affect cell proliferation under normal growth conditions. RNAseq analysis revealed that MEK inhibitors PD0325901 and selumetinib drastically altered cell cycle progression and cell migration networks under IGF1R signaling-mediated antiestrogen resistance. In a group of 219 patients with metastasized ER+ breast cancer, strong pMEK staining showed a significant correlation with no clinical benefit of first-line tamoxifen treatment. We propose a critical role for MEK activation in IGF1R signaling-mediated antiestrogen resistance and anticipate that dual-targeted therapy with a MEK inhibitor and antiestrogen could improve treatment outcome.
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Basu N, Narad P, Guptasarma ML, Tandon C, Das BC, Tandon S. Computational and In Vitro Approaches to Elucidate the Anti-cancer Effects of Arnica montana in Hormone-Dependent Breast Cancer. HOMEOPATHY 2022; 111:288-300. [PMID: 35790192 DOI: 10.1055/s-0042-1743565] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
BACKGROUND Breast cancer is the most common cancer in women worldwide. Use of homeopathic medicines for the treatment of cancers has increased in the last several years. Arnica montana is an anti-inflammatory homeopathic medicine used in traumatic conditions and because of this property we performed investigations for its potential as a chemotherapeutic agent against breast cancer. METHODS An ethanolic extract of Arnica montana (mother tincture, MT), prepared according to the Homoeopathic Pharmacopoeia of India, was characterized by gas chromatography-mass spectroscopy (GC-MS), followed by computational (in silico) analysis using molecular docking, to identify specific compounds that can bind and modulate the activity of key proteins involved in breast cancer survival and progression. To validate the in silico findings, in a controlled experiment breast cancer cells (MCF7) were treated in vitro with Arnica montana and the cytotoxic effects assessed by flowcytometry, fluorescence microscopy, scratch assay, clonogenic potential and gene expression analysis. RESULTS Phytochemical characterization of ethanolic extract of Arn MT by GC-MS allowed identification of several compounds. Caryophyllene oxide and 7-hydroxycadalene were selected for molecular docking studies, based on their potential drug-like properties. These compounds displayed selective binding affinity to some of the recognized target proteins of breast cancer, which included estrogen receptor alpha (ERα), progesterone receptor (PR), epidermal growth factor receptor (EGFR), mTOR (mechanistic target of rapamycin) and E-cadherin. In vitro studies revealed induction of apoptosis in MCF7 cells following treatment with Arn MT. Furthermore, treatment with Arn MT revealed its ability to inhibit migration and colony forming abilities of the cancer cells. CONCLUSION Considering the apoptotic and anti-migratory effects of Arnica montana in breast cancer cells in vitro, there is a need for this medicine to be further validated in an in vivo model.
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Affiliation(s)
- Nilanjana Basu
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Priyanka Narad
- Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
| | - Manni Luthra Guptasarma
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | - Bhudev Chandra Das
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida, Uttar Pradesh, India.,Amity University Punjab, Mohali, India
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Liu G, Xue J, Wang Y, Liu Z, Li X, Qu D, Su Z, Xu K, Qu X, Qu Z, Sun L, Cao M, Wang Y, Chen X, Yu J, Liu L, Deng Q, Zhao Y, Zhang L, Yang H. A randomized, open-label, two-cycle, two-crossover phase I clinical trial comparing the bioequivalence and safety of afatinib and Giotrif ® in healthy Chinese subjects. J Cancer Res Clin Oncol 2022; 149:2585-2593. [PMID: 35771264 DOI: 10.1007/s00432-022-04148-1] [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: 04/28/2022] [Accepted: 06/13/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Afatinib is an oral, irreversible ErbB family blocker. It binds covalently to the kinase domains of epidermal growth factor (EGFR), HER2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Our trial compared the bioequivalence and safety between afatinib produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and Giotrif® produced by Boehringer Ingelheim. METHODS Healthy Chinese subjects (N = 36) were randomly divided into two groups at a ratio of 1:1. There was a single dose per period of afatinib and Giotrif®. The washout was set as 14 days. Plasma drug concentrations of afatinib and Giotrif® were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for afatinib and Giotrif® were 102.80%, 101.83%, and 101.58%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both drugs showed a good safety profile during the trial. CONCLUSION This study showed that afatinib was bioequivalent to Giotrif® in healthy Chinese subjects with well safety. CHINESE CLINICAL TRIAL REGISTRY This trial is registered at the Chinese Clinical Trial website ( http://www.chinadrugtrials.org.cn/index.html # CTR20171160).
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Affiliation(s)
- Guangwen Liu
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Jinling Xue
- Department of Clinical Research Center, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Jiangsu, China
| | - Yanli Wang
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Zhengzhi Liu
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Xue Li
- Department of Clinical Research Center, Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Jiangsu, China
| | - Dongmei Qu
- Ansiterui Medical Technology Consulting Co., Ltd., Jilin, China
| | - Zhengjie Su
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Kaibo Xu
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Xinyao Qu
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Zhaojuan Qu
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Linlin Sun
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Mingming Cao
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Ying Wang
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Xuesong Chen
- Ansiterui Medical Technology Consulting Co., Ltd., Jilin, China
| | - Jing Yu
- Ansiterui Medical Technology Consulting Co., Ltd., Jilin, China
| | - Lang Liu
- Ansiterui Medical Technology Consulting Co., Ltd., Jilin, China
| | - Qiaohuan Deng
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China
| | - Yicheng Zhao
- Puheng Technology Co., Ltd. Shanghai, Shanghai, China
| | - Lixiu Zhang
- Lung Disease Center, Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, China.
| | - Haimiao Yang
- Phase I Clinical Trial Laboratory, Affiliated Hospital to Changchun University of Chinese Medicine, Jilin, China.
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Wang Y, Pan X, Li Y, Wang R, Yang Y, Jiang B, Sun G, Shao C, Wang M, Gong Y. CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-α36 axis. J Pathol 2021; 254:185-198. [PMID: 33638154 DOI: 10.1002/path.5657] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 01/28/2021] [Accepted: 02/24/2021] [Indexed: 12/24/2022]
Abstract
Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAMR and T47D-TAMR cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Yuxing Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Xiaohua Pan
- Department of Breast and Thyroid Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, PR China
| | - Yanjun Li
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Ru Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yuanyuan Yang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Baichun Jiang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Gongping Sun
- Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Changshun Shao
- State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, PR China
| | - Molin Wang
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
| | - Yaoqin Gong
- Key Laboratory of Experimental Teratology, Ministry of Education, Institute of Molecular Medicine and Genetics, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, PR China
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10
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Zhu W, Xu B. Overcoming resistance to endocrine therapy in hormone receptor-positive human epidermal growth factor receptor 2-negative (HR +/HER2 -) advanced breast cancer: a meta-analysis and systemic review of randomized clinical trials. Front Med 2021; 15:208-220. [PMID: 33175319 DOI: 10.1007/s11684-020-0795-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 04/17/2020] [Indexed: 01/30/2023]
Abstract
New targeted therapies have been developed to overcome resistance to endocrine therapy (ET) and improve the outcome of HR+/HER2- advanced breast cancer (ABC). We conducted a meta-analysis and systemic review on randomized controlled trials evaluating various targeted therapies in combination with ET in HR+/HER2- ABC. PUBMED and EMBASE databases were searched for eligible trials. Hazard ratios (HRs) for progression-free survival (PFS), odds ratios (ORs) for objective response rate (ORR), clinical benefit rate (CBR), and toxicity were meta-analyzed. Twenty-six studies with data on 10 347 patients were included and pooled. The addition of cyclin-dependent kinase 4/6 inhibitors to ET significantly improved median PFS (pooled HR = 0.547, P < 0.001), overall survival (pooled HR= 0.755, P < 0.001), and tumor response rates (ORR, pooled OR= 1.478, P < 0.001; CBR, pooled OR= 1.201, P < 0.001) with manageable toxicities (pooled OR= 3.280, P < 0.001). The mammalian targets of rapamycin inhibitors and exemestane were not clinically beneficial for this pooled population including ET-naïve and ET-resistant patients. Moderate improvement in PFS (pooled HR = 0.686, P < 0.001) yet pronounced toxicities (pooled OR = 2.154, P < 0.001) were noted in the combination of phosphatidylinositol-4,5-bisphosphate 3-kinase inhibitors with fulvestrant. Future studies are warranted to optimize the population and the dosing sequence of these available options.
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Affiliation(s)
- Wenjie Zhu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100021, China
| | - Binghe Xu
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing, 100021, China.
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11
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Lee N, Park MJ, Song W, Jeon K, Jeong S. Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer. Int J Mol Sci 2020; 21:ijms21228807. [PMID: 33233830 PMCID: PMC7699999 DOI: 10.3390/ijms21228807] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/17/2020] [Accepted: 11/19/2020] [Indexed: 12/11/2022] Open
Abstract
Approximately 70% of breast cancers, the leading cause of cancer-related mortality worldwide, are positive for the estrogen receptor (ER). Treatment of patients with luminal subtypes is mainly based on endocrine therapy. However, ER positivity is reduced and ESR1 mutations play an important role in resistance to endocrine therapy, leading to advanced breast cancer. Various methodologies for the detection of ESR1 mutations have been developed, and the most commonly used method is next-generation sequencing (NGS)-based assays (50.0%) followed by droplet digital PCR (ddPCR) (45.5%). Regarding the sample type, tissue (50.0%) was more frequently used than plasma (27.3%). However, plasma (46.2%) became the most used method in 2016-2019, in contrast to 2012-2015 (22.2%). In 2016-2019, ddPCR (61.5%), rather than NGS (30.8%), became a more popular method than it was in 2012-2015. The easy accessibility, non-invasiveness, and demonstrated usefulness with high sensitivity of ddPCR using plasma have changed the trends. When using these assays, there should be a comprehensive understanding of the principles, advantages, vulnerability, and precautions for interpretation. In the future, advanced NGS platforms and modified ddPCR will benefit patients by facilitating treatment decisions efficiently based on information regarding ESR1 mutations.
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Affiliation(s)
- Nuri Lee
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Min-Jeong Park
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Wonkeun Song
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
| | - Kibum Jeon
- Department of Laboratory Medicine, Hangang Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea;
| | - Seri Jeong
- Department of Laboratory Medicine, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul 07440, Korea; (N.L.); (M.-J.P.); (W.S.)
- Correspondence: ; Tel.: +82-845-5305
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12
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Ye J, Tian T, Chen X. The efficacy of gefitinib supplementation for breast cancer: A meta-analysis of randomized controlled studies. Medicine (Baltimore) 2020; 99:e22613. [PMID: 33120749 PMCID: PMC7581042 DOI: 10.1097/md.0000000000022613] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
INTRODUCTION The efficacy of gefitinib supplementation for breast cancer remains controversial. We conduct a systematic review and meta-analysis to explore the influence of gefitinib supplementation vs placebo on the efficacy of breast cancer. METHODS We have searched PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through February 2019 and included randomized controlled trials assessing the effect of gefitinib supplementation vs placebo on overall response for breast cancer patients. This meta-analysis was performed using the random-effect model. RESULTS Seven randomized controlled trials involving 927 patients were included in the meta-analysis. Overall, compared with control group for breast cancer, gefitinib supplementation revealed no obvious impact on complete response (risk ration [RR] = 1.19; 95% confidence interval [CI] = 0.58 to 2.44; P = .63), progressive disease (RR = 0.81; 95% CI = 0.59-1.11; P = .18), partial response (RR = 0.67; 95% CI = 0.36-1.25; P = .21), stable disease (RR = 1.02; 95% CI = 0.65-1.60; P = .92), nausea or vomiting (RR = 0.99; 95% CI = 0.73-1.33; P = .93), but was associated with increased incidence of diarrhea (RR = 2.80; 95% CI = 2.23-3.52; P < .00001), decreased incidence of hot flash (RR = 0.53; 95% CI = 0.37-0.78; P = .001), and improved incidence of adverse events (RR = 1.12; 95% CI = 1.05-1.19; P = .0006). CONCLUSIONS Gefitinib supplementation may provide no positive effect on complete response, progressive disease, partial response or stable disease for breast cancer patients, but with the increase in adverse events.
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Affiliation(s)
- Jing Ye
- Department of Surgery, Chongqing Yongchuan Health Center for Women and Children
| | - Tian Tian
- Department of General Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaopin Chen
- Department of General Surgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
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13
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Compensatory Estrogen Signal Is Capable of DNA Repair in Antiestrogen-Responsive Cancer Cells via Activating Mutations. JOURNAL OF ONCOLOGY 2020; 2020:5418365. [PMID: 32774370 PMCID: PMC7407016 DOI: 10.1155/2020/5418365] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 04/30/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
Cancer cells are embarrassed human cells exhibiting the remnants of same mechanisms for DNA stabilization like patients have in their healthy cells. Antiestrogens target the liganded activation of ERs, which is the principal means of genomic regulation in both patients and their tumors. The artificial blockade of liganded ER activation is an emergency situation promoting strong compensatory actions even in cancer cells. When tumor cells are capable of an appropriate upregulation of ER signaling resulting in DNA repair, a tumor response may be detected. In contrast, when ER signaling is completely inhibited, tumor cells show unrestrained proliferation, and tumor growth may be observed. The laboratory investigations of genomic mechanisms in antiestrogen-responsive and antiestrogen-unresponsive tumor cells have considerably enhanced our knowledge regarding the principal regulatory capacity of estrogen signaling. In antiestrogen-responsive tumor cells, a compensatory increased expression and liganded activation of estrogen receptors (ERs) result in an apoptotic death. Conversely, in antiestrogen resistant tumors exhibiting a complete blockade of liganded ER activation, a compensatory effort for unliganded ER activation is characteristic, conferred by the increased expression and activity of growth factor receptors. However, even extreme unliganded ER activation is incapable of DNA restoration when the liganded ER activation is completely blocked. Researchers mistakenly suspect even today that in tumors growing under antiestrogen treatment, the increased unliganded activation of estrogen receptor via activating mutations is an aggressive survival technique, whilst it is a compensatory effort against the blockade of liganded ER activation. The capacity of liganded ERs for genome modification in emergency states provides possibilities for estrogen/ER use in medical practice including cancer cure.
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14
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Sun M, Zhao S, Duan Y, Ma Y, Wang Y, Ji H, Zhang Q. GLUT1 participates in tamoxifen resistance in breast cancer cells through autophagy regulation. Naunyn Schmiedebergs Arch Pharmacol 2020; 394:205-216. [PMID: 32500187 DOI: 10.1007/s00210-020-01893-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 04/28/2020] [Indexed: 12/27/2022]
Abstract
Tamoxifen is an estrogen modulator widely used in the treatment of patients with ESR/ER-positive breast cancer; however, resistance limits its clinical application. Autophagy alterations have recently been suggested as a new mechanism for tamoxifen resistance. Glucose transporter 1 (GLUT1) has been reported to be associated with the development and metastasis of breast cancer, but the relationship among GLUT1, autophagy, and endocrine resistance remains unclear. Our present study found that GLUT1 expression and autophagy flux were upregulated in the tamoxifen-resistant breast cancer cell line MCF-7/TAMR-1 and that knockdown of GLUT1 promoted sensitization to tamoxifen. Moreover, knockdown of GLUT1 significantly decreased the enhancement of autophagy flux in tamoxifen-resistant cell lines. Furthermore, inhibiting autophagy in tamoxifen-resistant cells resulted in sensitization to tamoxifen. We conclude that GLUT1 contributes to tamoxifen resistance in breast cancer and that tamoxifen-resistant cells become resensitized to tamoxifen after GLUT1 silencing. These findings suggest GLUT1 as a new factor clinically associated with resistance to tamoxifen.
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Affiliation(s)
- Mengqi Sun
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150081, People's Republic of China
| | - Shu Zhao
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150081, People's Republic of China
| | - Yuchen Duan
- Department of Cardiology, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin, Heilongjiang, 150001, People's Republic of China
| | - Yumeng Ma
- Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150081, People's Republic of China
| | - Yicheng Wang
- College of Bioinformatics Science and Technology, Harbin Medical University, 157 Baojian Road, Harbin, Heilongjiang, 150081, People's Republic of China
| | - Hongfei Ji
- Heilongjiang Cancer Research and Prevention Institute, 150 Haping Road, Harbin, Heilongjiang, 150081, People's Republic of China
| | - Qingyuan Zhang
- Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, Heilongjiang, 150081, People's Republic of China.
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15
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Feng WW, Kurokawa M. Lipid metabolic reprogramming as an emerging mechanism of resistance to kinase inhibitors in breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2020; 3. [PMID: 32226926 PMCID: PMC7100881 DOI: 10.20517/cdr.2019.100] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.
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Affiliation(s)
- William W Feng
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
| | - Manabu Kurokawa
- Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Department of Biological Sciences, Kent State University, Kent, OH 44242, USA
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16
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Aggelis V, Johnston SRD. Advances in Endocrine-Based Therapies for Estrogen Receptor-Positive Metastatic Breast Cancer. Drugs 2019; 79:1849-1866. [DOI: 10.1007/s40265-019-01208-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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17
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Chen Y, Yang L, Liu J, Chen Z. Estrogen conjugated fluorescent silica nanoparticles as optical probes for breast cancer cells imaging. BIOMICROFLUIDICS 2019; 13:044113. [PMID: 31531151 PMCID: PMC6735662 DOI: 10.1063/1.5117769] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 08/15/2019] [Indexed: 06/10/2023]
Abstract
Fluorescent nanoparticles are promising tools for living cancer cell imaging and cancer targeting. In this study, estrogen conjugated dye-doped fluorescent nanoparticles (estrogen conjugated FNPs) were synthesized and characterized. The functionalized nanoparticles with low toxicity have shown high selectivity and sensitivity toward target cells. Based on the specific recognition between the estrogen and the estrogen receptor, estrogen conjugated FNPs have been employed as optical probes for specific targeting of estrogen receptor-positive cancer cells with fluorescence microscopy imaging technology. The results demonstrate that the estrogen conjugated FNPs can effectively recognize breast cancer cells with good sensitivity and exceptional photostability, which would offer a novel approach for the diagnosis of breast cancer cells, as well as a new method in detecting estrogen receptors.
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Affiliation(s)
| | | | - Jing Liu
- Key Laboratory of Combinatorial Biosynthesis and
Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of
Pharmaceutical Sciences, Wuhan 430072, China
| | - Zilin Chen
- Key Laboratory of Combinatorial Biosynthesis and
Drug Discovery (Wuhan University), Ministry of Education, and Wuhan University School of
Pharmaceutical Sciences, Wuhan 430072, China
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18
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Fan P, Jordan VC. New insights into acquired endocrine resistance of breast cancer. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:198-209. [PMID: 31815253 PMCID: PMC6897388 DOI: 10.20517/cdr.2019.13] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The translational research strategy of targeting estrogen receptor α (ERα) positive breast cancer and then using long term anti-hormone adjuvant therapy (5-10 years) has reduced recurrences and mortality. However, resistance continues to occur and improvements are required to build on the success of tamoxifen and aromatase inhibitors (AIs) established over the past 40 years. Further translational research has described the evolution of acquired resistance of breast cancer cell lines to long term estrogen deprivation that parallels clinical experience over years. Additionally, recent reports have identified mutations in the ERα obtained from the recurrences of AI treated patients. These mutations allow the ERα to activate without ligands and auto stimulate metastatic tumor growth. Furthermore, the new biology of estrogen-induced apoptosis in acquired resistant models in vitro and in vivo has been interrogated and applied to clinical trials. Inflammation and stress are emerging concepts occurring in the process of acquired resistance and estrogen-induced apoptosis with different mechanisms. In this review, we will present progress in the understanding of acquired resistance, focus on stress and inflammatory responses in the development of acquired resistance, and consider approaches to create new treatments to improve the treatment of breast cancer with endocrine resistance.
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Affiliation(s)
- Ping Fan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - V Craig Jordan
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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19
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Paplomata E, Zelnak A, Santa-Maria CA, Liu Y, Gogineni K, Li X, Moreno CS, Chen Z, Kaklamani V, O’Regan RM. Use of Everolimus and Trastuzumab in Addition to Endocrine Therapy in Hormone-Refractory Metastatic Breast Cancer. Clin Breast Cancer 2019; 19:188-196. [DOI: 10.1016/j.clbc.2018.12.017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Revised: 12/17/2018] [Accepted: 12/26/2018] [Indexed: 12/25/2022]
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20
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Lei JT, Gou X, Seker S, Ellis MJ. ESR1 alterations and metastasis in estrogen receptor positive breast cancer. ACTA ACUST UNITED AC 2019; 5. [PMID: 31106278 PMCID: PMC6519472 DOI: 10.20517/2394-4722.2019.12] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1 ) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.
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Affiliation(s)
- Jonathan T Lei
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Xuxu Gou
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sinem Seker
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Matthew J Ellis
- Interdepartmental Graduate Program in Translational Biology & Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA.,Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.,Departments of Medicine and Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA
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21
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Lin XR, Zhou XL, Feng Q, Pan XY, Song SL, Fang H, Lei J, Yang JL. CIK cell-based delivery of recombinant adenovirus KGHV500 carrying the anti-p21Ras scFv gene enhances the anti-tumor effect and safety in lung cancer. J Cancer Res Clin Oncol 2019; 145:1123-1132. [PMID: 30796510 DOI: 10.1007/s00432-019-02857-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 02/06/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Adenovirus (Ads) is one of the most popular vectors used in gene therapy for the treatment of cancer. However, systemic therapy is limited by circulating antiviral antibodies and poor viral delivery in vivo. In this study, we used cytokine-induced killer (CIK) cells as delivery vehicles of Ads KGHV500 carrying the anti-p21Ras scFv gene to treat Ras gene-related lung cancer and investigate the anti-tumor effect in vitro and in vivo. METHODS The human lung cancer cell line A549 was employed to investigate the anti-tumor activity of recombinant Ads KGHV500 harboring the anti-p21Ras scFv gene using MTT, wound healing, transwell invasion, and apoptosis assays in vitro. Next, CIK cells were used as delivery vehicles to deliver KGHV500 carrying the anti-p21Ras scFv gene to treat A549-transplanted tumors in nude mice, and viral replication, p21Ras scFv expression, and the therapeutic efficacy were assessed. RESULTS In vitro studies showed that KGHV500 had potent anti-tumor activity. In addition, in vivo, this combination therapy significantly inhibited the growth of lung cancer xenografts compared with mice treated with KGHV500 alone. KGHV500 and anti-p21Ras scFv were observed in tumor tissue, but were nearly undetectable in normal tissues. CONCLUSIONS The co-delivery of anti-p21Ras scFv by CIK cells and KGHV500 could increase the anti-tumor effect and safety, and possess considerable advantages for the treatment of Ras-related cancer.
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Affiliation(s)
- Xin-Rui Lin
- Graduate School, Kunming Medical University, Chenggong District, Kunming, People's Republic of China
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Xin-Liang Zhou
- Department of Pathology, Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China
| | - Qiang Feng
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Xin-Yan Pan
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Shu-Ling Song
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Hong Fang
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Jin Lei
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China
| | - Ju-Lun Yang
- Graduate School, Kunming Medical University, Chenggong District, Kunming, People's Republic of China.
- Department of Pathology, 920th Hospital of the Joint Logistics Support Force of PLA, 212 Daguan Road, Kunming, 650032, Yunnan, People's Republic of China.
- Department of Pathology, Medical Faculty, Kunming University of Science and Technology, Kunming, People's Republic of China.
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22
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Moran T, Quiroga V, Cirauqui B, Vila L, Gil-Moreno M, Carcereny E, Margeli M, Muñoz-Marmol A, Mate JL, Velarde JM, Molina MA, Rosell R. A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and EGFR-Mutant Non-Small Cell Lung Cancer. Oncol Res Treat 2019; 42:107-114. [PMID: 30799393 DOI: 10.1159/000495666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 11/19/2018] [Indexed: 01/28/2023]
Abstract
BACKGROUND Second primary malignancies (SPM) in the lung are not common in breast cancer (BC) patients. EGFR-mutant lung cancer (LC) is a separate molecular subset, and the co-existence of EGFR-mutant LC and BC has not been explored. We hypothesized that EGFR-mutant LC patients could have higher rates of primary BC than those with EGFR-wild type (WT). METHODS We collected data on clinical and molecular characteristics and outcomes of female patients with LC and a previous or simultaneous history of primary BC treated in our hospital from 2008 to 2014. RESULTS Data on treatment, follow-up, and EGFR mutation status were available for 356 patients. 17.7% (11/62) of patients with EGFR mutations had BC, compared to 1.02% (3/294) of EGFR-WT patients (p < 0.001). Both tumors were metachronous in 81.8%, with LC diagnosed 9 years after the diagnosis of BC. 5 of the 6 (83.3%) BC patients treated with radiotherapy developed LC in an area within the radiation field. No EGFR mutations were detected in BC tissue and no HER2 expression was detected in LC samples. CONCLUSION SPM in the lung and breast occur more frequently among EGFR-mutant compared to EGFR-WT LC patients. Radiotherapy for BC may increase the risk of developing primary LC.
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23
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Rani A, Stebbing J, Giamas G, Murphy J. Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy. Front Endocrinol (Lausanne) 2019; 10:245. [PMID: 31178825 PMCID: PMC6543000 DOI: 10.3389/fendo.2019.00245] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 03/28/2019] [Indexed: 12/24/2022] Open
Abstract
The importance and role of the estrogen receptor (ER) pathway has been well-documented in both breast cancer (BC) development and progression. The treatment of choice in women with metastatic breast cancer (MBC) is classically divided into a variety of endocrine therapies, 3 of the most common being: selective estrogen receptor modulators (SERM), aromatase inhibitors (AI) and selective estrogen receptor down-regulators (SERD). In a proportion of patients, resistance develops to endocrine therapy due to a sophisticated and at times redundant interference, at the molecular level between the ER and growth factor. The progression to endocrine resistance is considered to be a gradual, step-wise process. Several mechanisms have been proposed but thus far none of them can be defined as the complete explanation behind the phenomenon of endocrine resistance. Although multiple cellular, molecular and immune mechanisms have been and are being extensively studied, their individual roles are often poorly understood. In this review, we summarize current progress in our understanding of ER biology and the molecular mechanisms that predispose and determine endocrine resistance in breast cancer patients.
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Affiliation(s)
- Aradhana Rani
- School of Life Sciences, University of Westminster, London, United Kingdom
- *Correspondence: Aradhana Rani
| | - Justin Stebbing
- Department of Surgery and Cancer, Imperial College London, London, United Kingdom
| | - Georgios Giamas
- Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, Brighton, United Kingdom
| | - John Murphy
- School of Life Sciences, University of Westminster, London, United Kingdom
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24
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Mao SPH, Park M, Cabrera RM, Christin JR, Karagiannis GS, Oktay MH, Zaiss DMW, Abrams SI, Guo W, Condeelis JS, Kenny PA, Segall JE. Loss of amphiregulin reduces myoepithelial cell coverage of mammary ducts and alters breast tumor growth. Breast Cancer Res 2018; 20:131. [PMID: 30367629 PMCID: PMC6203982 DOI: 10.1186/s13058-018-1057-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/02/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Amphiregulin (AREG), a ligand of the epidermal growth factor receptor, is not only essential for proper mammary ductal development, but also associated with breast cancer proliferation and growth. In the absence of AREG, mammary ductal growth is stunted and fails to expand. Furthermore, suppression of AREG expression in estrogen receptor-positive breast tumor cells inhibits in-vitro and in-vivo growth. METHODS We crossed AREG-null (AREG-/-) mice with the murine luminal B breast cancer model, MMTV-PyMT (PyMT), to generate spontaneous breast tumors that lack AREG (AREG-/- PyMT). We evaluated tumor growth, cytokeratin-8 (K8)-positive luminal cells, cytokeratin-14 (K14)-positive myoepithelial cells, and expression of AREG, Ki67, and PyMT. Primary myoepithelial cells from nontumor-bearing AREG+/+ mice underwent fluorescence-activated cell sorting and were adapted to culture for in-vitro coculture studies with AT-3 cells, a cell line derived from C57Bl/6 PyMT mammary tumors. RESULTS Intriguingly, PyMT-induced lesions progress more rapidly in AREG-/- mice than in AREG+/+ mice. Quantification of K8+ luminal and K14+ myoepithelial cells in non-PyMT AREG-/- mammary glands showed fewer K14+ cells and a thinner myoepithelial layer. Study of AT-3 cells indicated that coculture with myoepithelial cells or exposure to AREG, epidermal growth factor, or basic fibroblast growth factor can suppress PyMT expression. Late-stage AREG-/- PyMT tumors are significantly less solid in structure, with more areas of papillary and cystic growth. Papillary areas appear to be both less proliferative and less necrotic. In The Cancer Genome Atlas database, luminal-B invasive papillary carcinomas have lower AREG expression than luminal B invasive ductal carcinomas. CONCLUSIONS Our study has revealed a previously unknown role of AREG in myoepithelial cell development and PyMT expression. AREG expression is essential for proper myoepithelial coverage of mammary ducts. Both AREG and myoepithelial cells can suppress PyMT expression. We find that lower AREG expression is associated with invasive papillary breast cancer in both the MMTV-PyMT model and human breast cancer.
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MESH Headings
- Amphiregulin/genetics
- Amphiregulin/metabolism
- Animals
- Antigens, Polyomavirus Transforming/genetics
- Antigens, Polyomavirus Transforming/metabolism
- Cell Line, Tumor
- Cell Proliferation
- Epithelial Cells/pathology
- Epithelial Cells/virology
- Female
- Humans
- Mammary Glands, Animal/cytology
- Mammary Glands, Animal/pathology
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/pathology
- Mammary Neoplasms, Experimental/virology
- Mammary Tumor Virus, Mouse/genetics
- Mammary Tumor Virus, Mouse/pathogenicity
- Mice
- Mice, Inbred C57BL
- Mice, Transgenic
- Neoplasm Invasiveness/pathology
- Polyomavirus/genetics
- Polyomavirus/immunology
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Affiliation(s)
- Serena P. H. Mao
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
| | - Minji Park
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
| | - Ramon M. Cabrera
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
| | - John R. Christin
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - George S. Karagiannis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - Maja H. Oktay
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - Dietmar M. W. Zaiss
- Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK
| | - Scott I. Abrams
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263 USA
| | - Wenjun Guo
- Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - John S. Condeelis
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
- Integrated Imaging Program, Albert Einstein College of Medicine, Bronx, NY 10461 USA
| | - Paraic A. Kenny
- Kabara Cancer Research Institute, Gundersen Medical Foundation, La Crosse, WI 54601 USA
| | - Jeffrey E. Segall
- Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1301 Morris Park Avenue, Bronx, NY 10461 USA
- Gruss Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY 10461 USA
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25
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Sudhan DR, Schwarz LJ, Guerrero-Zotano A, Formisano L, Nixon MJ, Croessmann S, González Ericsson PI, Sanders M, Balko JM, Avogadri-Connors F, Cutler RE, Lalani AS, Bryce R, Auerbach A, Arteaga CL. Extended Adjuvant Therapy with Neratinib Plus Fulvestrant Blocks ER/HER2 Crosstalk and Maintains Complete Responses of ER +/HER2 + Breast Cancers: Implications to the ExteNET Trial. Clin Cancer Res 2018; 25:771-783. [PMID: 30274983 DOI: 10.1158/1078-0432.ccr-18-1131] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Revised: 08/09/2018] [Accepted: 09/26/2018] [Indexed: 11/16/2022]
Abstract
PURPOSE The phase III ExteNET trial showed improved invasive disease-free survival in patients with HER2+ breast cancer treated with neratinib versus placebo after trastuzumab-based adjuvant therapy. The benefit from neratinib appeared to be greater in patients with ER+/HER2+ tumors. We thus sought to discover mechanisms that may explain the benefit from extended adjuvant therapy with neratinib.Experimental Design: Mice with established ER+/HER2+ MDA-MB-361 tumors were treated with paclitaxel plus trastuzumab ± pertuzumab for 4 weeks, and then randomized to fulvestrant ± neratinib treatment. The benefit from neratinib was evaluated by performing gene expression analysis for 196 ER targets, ER transcriptional reporter assays, and cell-cycle analyses. RESULTS Mice receiving "extended adjuvant" therapy with fulvestrant/neratinib maintained a complete response, whereas those treated with fulvestrant relapsed rapidly. In three ER+/HER2+ cell lines (MDA-MB-361, BT-474, UACC-893) but not in ER+/HER2- MCF7 cells, treatment with neratinib induced ER reporter transcriptional activity, whereas treatment with fulvestrant resulted in increased HER2 and EGFR phosphorylation, suggesting compensatory reciprocal crosstalk between the ER and ERBB RTK pathways. ER transcriptional reporter assays, gene expression, and immunoblot analyses showed that treatment with neratinib/fulvestrant, but not fulvestrant, potently inhibited growth and downregulated ER reporter activity, P-AKT, P-ERK, and cyclin D1 levels. Finally, similar to neratinib, genetic and pharmacologic inactivation of cyclin D1 enhanced fulvestrant action against ER+/HER2+ breast cancer cells. CONCLUSIONS These data suggest that ER blockade leads to reactivation of ERBB RTKs and thus extended ERBB blockade is necessary to achieve durable clinical outcomes in patients with ER+/HER2+ breast cancer.
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Affiliation(s)
- Dhivya R Sudhan
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Luis J Schwarz
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Oncosalud-AUNA, Lima, Peru
| | - Angel Guerrero-Zotano
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Luigi Formisano
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Mellissa J Nixon
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Sarah Croessmann
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Paula I González Ericsson
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Melinda Sanders
- Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Pathology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Justin M Balko
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | | | | | | | | | | | - Carlos L Arteaga
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee. .,Breast Cancer Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.,Harold C. Simmons Cancer Center, UT Southwestern Medical Center, Dallas, Texas
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26
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Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N, Cai Y, Bielski CM, Donoghue MTA, Jonsson P, Penson A, Shen R, Pareja F, Kundra R, Middha S, Cheng ML, Zehir A, Kandoth C, Patel R, Huberman K, Smyth LM, Jhaveri K, Modi S, Traina TA, Dang C, Zhang W, Weigelt B, Li BT, Ladanyi M, Hyman DM, Schultz N, Robson ME, Hudis C, Brogi E, Viale A, Norton L, Dickler MN, Berger MF, Iacobuzio-Donahue CA, Chandarlapaty S, Scaltriti M, Reis-Filho JS, Solit DB, Taylor BS, Baselga J. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell 2018; 34:427-438.e6. [PMID: 30205045 PMCID: PMC6327853 DOI: 10.1016/j.ccell.2018.08.008] [Citation(s) in RCA: 685] [Impact Index Per Article: 97.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Revised: 07/15/2018] [Accepted: 08/09/2018] [Indexed: 02/06/2023]
Abstract
We integrated the genomic sequencing of 1,918 breast cancers, including 1,501 hormone receptor-positive tumors, with detailed clinical information and treatment outcomes. In 692 tumors previously exposed to hormonal therapy, we identified an increased number of alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and in the estrogen receptor transcriptional machinery. Activating ERBB2 mutations and NF1 loss-of-function mutations were more than twice as common in endocrine resistant tumors. Alterations in other MAPK pathway genes (EGFR, KRAS, among others) and estrogen receptor transcriptional regulators (MYC, CTCF, FOXA1, and TBX3) were also enriched. Altogether, these alterations were present in 22% of tumors, mutually exclusive with ESR1 mutations, and associated with a shorter duration of response to subsequent hormonal therapies.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Agents, Hormonal/pharmacology
- Antineoplastic Agents, Hormonal/therapeutic use
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics
- Breast Neoplasms/pathology
- Breast Neoplasms, Male/drug therapy
- Breast Neoplasms, Male/genetics
- Breast Neoplasms, Male/pathology
- Drug Resistance, Neoplasm/genetics
- Estrogen Receptor alpha/genetics
- Estrogen Receptor alpha/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Genomics
- Humans
- MAP Kinase Signaling System/genetics
- Male
- Middle Aged
- Mutation
- Neurofibromin 1/genetics
- Neurofibromin 1/metabolism
- Prospective Studies
- Receptor, ErbB-2/genetics
- Receptor, ErbB-2/metabolism
- Receptors, Progesterone/genetics
- Receptors, Progesterone/metabolism
- Young Adult
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Affiliation(s)
- Pedram Razavi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Matthew T Chang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Guotai Xu
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Chaitanya Bandlamudi
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Dara S Ross
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Neil Vasan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Yanyan Cai
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Craig M Bielski
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mark T A Donoghue
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Philip Jonsson
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Alexander Penson
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ronglai Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Fresia Pareja
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ritika Kundra
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Sumit Middha
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael L Cheng
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ahmet Zehir
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Cyriac Kandoth
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ruchi Patel
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Kety Huberman
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Lillian M Smyth
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Komal Jhaveri
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Shanu Modi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Tiffany A Traina
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Chau Dang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Wen Zhang
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Britta Weigelt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Bob T Li
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Marc Ladanyi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David M Hyman
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Nikolaus Schultz
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mark E Robson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Clifford Hudis
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Edi Brogi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Agnes Viale
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Larry Norton
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Maura N Dickler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Michael F Berger
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Christine A Iacobuzio-Donahue
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Sarat Chandarlapaty
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Maurizio Scaltriti
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Jorge S Reis-Filho
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David B Solit
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - Barry S Taylor
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| | - José Baselga
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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27
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Siersbæk R, Kumar S, Carroll JS. Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer. Genes Dev 2018; 32:1141-1154. [PMID: 30181360 PMCID: PMC6120708 DOI: 10.1101/gad.316646.118] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER+ breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.
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Affiliation(s)
- Rasmus Siersbæk
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
| | - Sanjeev Kumar
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
- Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom
| | - Jason S Carroll
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, United Kingdom
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28
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Yau THL, Cheung KL. Optimising endocrine therapy in postmenopausal women with advanced breast cancer. Endocr Relat Cancer 2018; 25:705-721. [PMID: 29674428 DOI: 10.1530/erc-18-0021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 04/19/2018] [Indexed: 01/01/2023]
Abstract
Hormone receptor-positive breast cancer is commonly treated with endocrine therapy (ET); however, over time, cancer cells can develop endocrine resistance. This review aims to document combination therapy and sequential therapy in the use of endocrine agents and targeted agents, by conducting two systematic searches using four databases: Cochrane Library, MEDLINE, EMBASE and Web of Science. A total of 26 studies that covered combination therapy were obtained and included for the review. Fourteen were phase III documenting combinations of mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase (PI3K), vascular endothelial growth factor receptor, human epidermal growth factor receptor 2 and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. The remaining studies were of phase II nature that reported combinations involving inhibitors in mTOR, endothelial growth factor receptor, CDK4/6 and TKI. Interesting findings in inhibitor combinations involving CDK4/6, mTOR and PI3K suggest clinical activity that can overcome endocrine resistance. On the other hand, there were 0 studies that covered sequential therapy. Overall findings showed that combination therapy improved treatment efficacy over monotherapy in postmenopausal patients with hormone receptor-positive advanced breast cancer. Inevitably, the benefits are accompanied with increased toxicity. To optimise ET, further research into combinations and effective patient selection will need to be defined. Additionally, this review warrants future studies to explore sequential therapy.
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29
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AlFakeeh A, Brezden-Masley C. Overcoming endocrine resistance in hormone receptor-positive breast cancer. ACTA ACUST UNITED AC 2018; 25:S18-S27. [PMID: 29910644 DOI: 10.3747/co.25.3752] [Citation(s) in RCA: 94] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Endocrine therapy, a major modality in the treatment of hormone receptor (hr)-positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)-targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways-most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and PIK3CA mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.
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Affiliation(s)
- A AlFakeeh
- Division of Hematology/Oncology, St. Michael's Hospital, University of Toronto, Toronto, ON.,King Fahad Medical City, Comprehensive Cancer Centre, Riyadh, Saudi Arabia
| | - C Brezden-Masley
- Division of Hematology/Oncology, St. Michael's Hospital, University of Toronto, Toronto, ON.,Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON
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30
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Ribas R, Pancholi S, Rani A, Schuster E, Guest SK, Nikitorowicz-Buniak J, Simigdala N, Thornhill A, Avogadri-Connors F, Cutler RE, Lalani AS, Dowsett M, Johnston SR, Martin LA. Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer. Breast Cancer Res 2018; 20:44. [PMID: 29880014 PMCID: PMC5992820 DOI: 10.1186/s13058-018-0983-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 05/10/2018] [Indexed: 12/19/2022] Open
Abstract
Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER. Electronic supplementary material The online version of this article (10.1186/s13058-018-0983-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ricardo Ribas
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Sunil Pancholi
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Aradhana Rani
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Eugene Schuster
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Stephanie K Guest
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Joanna Nikitorowicz-Buniak
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Nikiana Simigdala
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK
| | - Allan Thornhill
- Centre for Cancer Imaging, The Institute of Cancer Research, Sutton, SM2 5NG, UK
| | | | | | | | - Mitch Dowsett
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.,The Ralph Lauren Centre for Breast Cancer Research, The Royal Marsden Hospital, London, SW3 6JJ, UK
| | | | - Lesley-Ann Martin
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, SW7 3RP, UK.
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31
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Mishra RR, Belder N, Ansari SA, Kayhan M, Bal H, Raza U, Ersan PG, Tokat ÜM, Eyüpoğlu E, Saatci Ö, Jandaghi P, Wiemann S, Üner A, Cekic C, Riazalhosseini Y, Şahin Ö. Reactivation of cAMP Pathway by PDE4D Inhibition Represents a Novel Druggable Axis for Overcoming Tamoxifen Resistance in ER-positive Breast Cancer. Clin Cancer Res 2018; 24:1987-2001. [PMID: 29386221 DOI: 10.1158/1078-0432.ccr-17-2776] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2017] [Revised: 12/06/2017] [Accepted: 01/25/2018] [Indexed: 11/16/2022]
Abstract
Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer; however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance.Experimental Design: Whole-transcriptome sequencing, downstream pathway analysis, and drug repositioning approaches were used to identify novel modulators [here: phosphodiesterase 4D (PDE4D)] of tamoxifen resistance. Clinical data involving tamoxifen-treated patients with ER-positive breast cancer were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo Cytobiology, biochemistry, and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance.Results: PDE4D, which hydrolyzes cyclic AMP (cAMP), was significantly overexpressed in both MCF-7 and T47D tamoxifen-resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated patients with breast cancer (n = 469, P = 0.0036 for DMFS; n = 561, P = 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n = 132, P = 0.049). Inhibition of PDE4D by either siRNAs or pharmacologic inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded protein response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, acetylsalicylic acid (aspirin) was predicted to be a tamoxifen sensitizer using a drug repositioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivoConclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis. Clin Cancer Res; 24(8); 1987-2001. ©2018 AACR.
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Affiliation(s)
- Rasmi R Mishra
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Nevin Belder
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Suhail A Ansari
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Merve Kayhan
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Hilal Bal
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Umar Raza
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Pelin G Ersan
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Ünal M Tokat
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Erol Eyüpoğlu
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Özge Saatci
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Pouria Jandaghi
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
| | - Stefan Wiemann
- Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ayşegül Üner
- Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Caglar Cekic
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey
| | - Yasser Riazalhosseini
- Department of Human Genetics, McGill University, Montreal, Quebec, Canada
- McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
| | - Özgür Şahin
- Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey.
- National Nanotechnology Research Center (UNAM), Bilkent University, Ankara, Turkey
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Lee MH, Koh D, Na H, Ka NL, Kim S, Kim HJ, Hong S, Shin YK, Seong JK, Lee MO. MTA1 is a novel regulator of autophagy that induces tamoxifen resistance in breast cancer cells. Autophagy 2018; 14:812-824. [PMID: 29130361 PMCID: PMC6070012 DOI: 10.1080/15548627.2017.1388476] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 09/18/2017] [Accepted: 10/02/2017] [Indexed: 12/22/2022] Open
Abstract
Tamoxifen is commonly used to treat patients with ESR/ER-positive breast cancer, but its therapeutic benefit is limited by the development of resistance. Recently, alterations in macroautophagy/autophagy function were demonstrated to be a potential mechanism for tamoxifen resistance. Although MTA1 (metastasis-associated 1) has been implicated in breast tumorigenesis and metastasis, its role in endocrine resistance has not been studied. Here, we report that the level of MTA1 expression was upregulated in the tamoxifen resistant breast cancer cell lines MCF7/TAMR and T47D/TR, and knockdown of MTA1 sensitized the cells to 4-hydroxytamoxifen (4OHT). Moreover, knockdown of MTA1 significantly decreased the enhanced autophagy flux in the tamoxifen resistant cell lines. To confirm the role of MTA1 in the development of tamoxifen resistance, we established a cell line, MCF7/MTA1, which stably expressed MTA1. Compared with parental MCF7, MCF7/MTA1 cells were more resistant to 4OHT-induced growth inhibition in vitro and in vivo, and showed increased autophagy flux and higher numbers of autophagosomes. Knockdown of ATG7 or cotreatment with hydroxychloroquine, an autophagy inhibitor, restored sensitivity to 4OHT in both the MCF7/MTA1 and tamoxifen resistant cells. In addition, AMP-activated protein kinase (AMPK) was activated, probably because of an increased AMP:ATP ratio and decreased expression of mitochondrial electron transport complex components. Finally, publicly available breast cancer patient datasets indicate that MTA1 levels correlate with poor prognosis and development of recurrence in patients with breast cancer treated with tamoxifen. Overall, our findings demonstrated that MTA1 induces AMPK activation and subsequent autophagy that could contribute to tamoxifen resistance in breast cancer.
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Affiliation(s)
- Min-Ho Lee
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Dahae Koh
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Hyelin Na
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Na-Lee Ka
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Seungsu Kim
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Hyeon-Ji Kim
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Sungyoul Hong
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Young Kee Shin
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Je Kyung Seong
- Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, Seoul National University and Korea Mouse Phenotyping Center, 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
| | - Mi-Ock Lee
- Department of Pharmacy, College of Pharmacy and Bio-MAX Institute, Seoul National University 1 Gwanak-ro, Gwanak-gu, Seoul, Korea
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Severson TM, Nevedomskaya E, Peeters J, Kuilman T, Krijgsman O, van Rossum A, Droog M, Kim Y, Koornstra R, Beumer I, Glas AM, Peeper D, Wesseling J, Simon IM, Wessels L, Linn SC, Zwart W. Neoadjuvant tamoxifen synchronizes ERα binding and gene expression profiles related to outcome and proliferation. Oncotarget 2017; 7:33901-18. [PMID: 27129152 PMCID: PMC5085127 DOI: 10.18632/oncotarget.8983] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 04/13/2016] [Indexed: 12/17/2022] Open
Abstract
Estrogen receptor alpha (ERα)-positive breast cancers are frequently treated with tamoxifen, but resistance is common. It remains elusive how tamoxifen resistance occurs and predictive biomarkers for treatment outcome are needed. Because most biomarker discovery studies are performed using pre-treatment surgical resections, the effects of tamoxifen therapy directly on the tumor cell in vivo remain unexamined. In this study, we assessed DNA copy number, gene expression profiles and ERα/chromatin binding landscapes on breast tumor specimens, both before and after neoadjuvant tamoxifen treatment. We observed neoadjuvant tamoxifen treatment synchronized ERα/chromatin interactions and downstream gene expression, indicating that hormonal therapy reduces inter-tumor molecular variability. ERα-synchronized sites are associated with dynamic FOXA1 action at these sites, which is under control of growth factor signaling. Genes associated with tamoxifen-synchronized sites are capable of differentiating patients for tamoxifen benefit. Due to the direct effects of therapeutics on ERα behavior and transcriptional output, our study highlights the added value of biomarker discovery studies after neoadjuvant drug exposure.
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Affiliation(s)
- Tesa M Severson
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Ekaterina Nevedomskaya
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.,Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | | | - Thomas Kuilman
- Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Oscar Krijgsman
- Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Annelot van Rossum
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Marjolein Droog
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Yongsoo Kim
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.,Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Rutger Koornstra
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, GA, The Netherlands
| | | | | | - Daniel Peeper
- Division of Molecular Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Jelle Wesseling
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | | | - Lodewyk Wessels
- Division of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
| | - Sabine C Linn
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.,Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands.,Department of Pathology, University Medical Center Utrecht, CX, The Netherlands
| | - Wilbert Zwart
- Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, CX, The Netherlands
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Araki K, Miyoshi Y. Mechanism of resistance to endocrine therapy in breast cancer: the important role of PI3K/Akt/mTOR in estrogen receptor-positive, HER2-negative breast cancer. Breast Cancer 2017; 25:392-401. [PMID: 29086897 DOI: 10.1007/s12282-017-0812-x] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 10/26/2017] [Indexed: 12/18/2022]
Abstract
Endocrine therapy is a crucial treatment for estrogen receptor-positive (ER+) breast cancer, with proven clinical benefits. However, adaptive mechanisms emerge in the tumor, causing resistance to endocrine therapy. A better understanding of resistance mechanisms is needed to overcome this problem and to develop new, precise treatment strategies. Accumulating genetic and cancer biological studies demonstrate the importance of understanding the PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer. PIK3CA (which encodes phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit α) is frequently mutated in breast cancer, and 30% of advanced ER+ HER2- breast cancers have an activating PIK3CA mutation. AKT1 mutations (E17K) have been found in 1.4-8% of breast cancer patients. ER+ breast cancer patients preferentially demonstrate gain of CCND1 (cyclin D1; 58% in luminal B vs. 29% in luminal A) and CDK4 (25% in luminal B vs. 14% in luminal A) and loss of CDKN2A (p16) and CDKN2C (p18), which are negatively regulated with the cell cycle and are correlated with the CDK4/6/RB pathway. Abnormalities in PI3K/Akt/mTOR and CDK4/6/RB pathways due to genetic alterations result in deregulated kinase activity and malignant transformation. This review focuses on the recent reports of the essential role of PI3K/Akt/mTOR and CDK4/6/RB pathways in ER+ HER2- breast cancer.
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Affiliation(s)
- Kazuhiro Araki
- Division of Breast and Endocrine, Department of Surgery, Cancer Center, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Yasuo Miyoshi
- Division of Breast and Endocrine, Department of Surgery, Cancer Center, Hyogo College of Medicine, 1-1 Mukogawa, Nishinomiya, Hyogo, 663-8501, Japan
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35
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Mercatali L, La Manna F, Miserocchi G, Liverani C, De Vita A, Spadazzi C, Bongiovanni A, Recine F, Amadori D, Ghetti M, Ibrahim T. Tumor-Stroma Crosstalk in Bone Tissue: The Osteoclastogenic Potential of a Breast Cancer Cell Line in a Co-Culture System and the Role of EGFR Inhibition. Int J Mol Sci 2017; 18:ijms18081655. [PMID: 28758931 PMCID: PMC5578045 DOI: 10.3390/ijms18081655] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 07/21/2017] [Accepted: 07/25/2017] [Indexed: 12/21/2022] Open
Abstract
Although bone metastases represent a major challenge in the natural history of breast cancer (BC), the complex interactions involved have hindered the development of robust in vitro models. The aim of this work is the development of a preclinical model of cancer and bone stromal cells to mimic the bone microenvironment. We studied the effects on osteoclastogenesis of BC cells and Mesenchymal stem cells (MSC) cultured alone or in combination. We also analyzed: (a) whether the blockade of the Epithelial Growth Factor Receptor (EGFR) pathway modified their influence on monocytes towards differentiation, and (b) the efficacy of bone-targeted therapy on osteoclasts. We evaluated the osteoclastogenesis modulation of human peripheral blood monocytes (PBMC) indirectly induced by the conditioned medium (CM) of the human BC cell line SCP2, cultured singly or with MSC. Osteoclastogenesis was evaluated by TRAP analysis. The effect of the EGFR blockade was assessed by treating the cells with gefitinib, and analyzed with the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western Blot (WB). We observed that SCP2 co-cultured with MSC increased the differentiation of PBMC. This effect was underpinned upon pre-treatment of the co-culture with gefitinib. Co-culture of SCP2 with MSC increased the expression of both the bone-related marker Receptor Activator of Nuclear Factor κB (RANK) and EGFR in BC cells. These upregulations were not affected by the EGFR blockade. The effects of the CM obtained by the cells treated with gefitinib in combination with the treatment of the preosteoclasts with the bone-targeted agents and everolimus enhanced the inhibition of the osteoclastogenesis. Finally, we developed a fully human co-culture system of BC cells and bone progenitor cells. We observed that the interaction of MSC with cancer cells induced in the latter molecular changes and a higher power of inducing osteoclastogenesis. We found that blocking EGFR signaling could be an efficacious strategy for breaking the interactions between cancer and bone cells in order to inhibit bone metastasis.
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Affiliation(s)
- Laura Mercatali
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Federico La Manna
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giacomo Miserocchi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Chiara Liverani
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Alessandro De Vita
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Chiara Spadazzi
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Alberto Bongiovanni
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Federica Recine
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Dino Amadori
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Martina Ghetti
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
- Biomedical and Neuromotor Sciences Department, University of Bologna, 40123 Bologna, Italy.
| | - Toni Ibrahim
- Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
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Turner NC, Neven P, Loibl S, Andre F. Advances in the treatment of advanced oestrogen-receptor-positive breast cancer. Lancet 2017; 389:2403-2414. [PMID: 27939057 DOI: 10.1016/s0140-6736(16)32419-9] [Citation(s) in RCA: 143] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Revised: 07/28/2016] [Accepted: 08/24/2016] [Indexed: 12/12/2022]
Abstract
Oestrogen-receptor-positive breast cancer is the most common subtype of breast cancer. Endocrine therapies that target the dependence of this subtype on the oestrogen receptor have substantial activity, yet the development of resistance to therapy is inevitable in advanced cancer. Major progress has been made in identifying the drivers of oestrogen-receptor-positive breast cancer and the mechanisms of resistance to endocrine therapy. This progress has translated into major advances in the treatment of advanced breast cancer, with several targeted therapies that enhance the efficacy of endocrine therapy; inhibitors of mTOR and inhibitors of the cyclin-dependent kinases CDK4 and CDK6 substantially improve progression-free survival. A new wave of targeted therapies is being developed, including inhibitors of PI3K, AKT, and HER2, and a new generation of oestrogen-receptor degraders. Considerable challenges remain in patient selection, deciding on the most appropriate order in which to administer therapies, and establishing whether cross-resistance occurs between therapies.
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Affiliation(s)
| | - Patrick Neven
- Multidisciplinary Breast Centre and Department of Gynaecological Oncology, University Hospitals Leuven, Department of Oncology, Leuven, Belgium
| | - Sibylle Loibl
- German Breast Group (GBG), c/o GBG Forschungs GmbH, Neu-Isenburg, Germany; Centre for Haematology and Oncology, Bethanien, Frankfurt, Germany.
| | - Fabrice Andre
- INSERM U981, Gustave Roussy Cancer Center, Université Paris Sud, Villejuif, France
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Matikas A, Foukakis T, Bergh J. Tackling endocrine resistance in ER-positive HER2-negative advanced breast cancer: A tale of imprecision medicine. Crit Rev Oncol Hematol 2017; 114:91-101. [DOI: 10.1016/j.critrevonc.2017.04.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Revised: 03/28/2017] [Accepted: 04/04/2017] [Indexed: 12/29/2022] Open
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Guerrero-Zotano AL, Arteaga CL. Neoadjuvant Trials in ER + Breast Cancer: A Tool for Acceleration of Drug Development and Discovery. Cancer Discov 2017; 7:561-574. [PMID: 28495849 PMCID: PMC5497752 DOI: 10.1158/2159-8290.cd-17-0228] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/03/2017] [Accepted: 04/17/2017] [Indexed: 12/17/2022]
Abstract
Neoadjuvant therapy trials offer an excellent strategy for drug development and discovery in breast cancer, particularly in triple-negative and HER2-overexpressing subtypes, where pathologic complete response is a good surrogate of long-term patient benefit. For estrogen receptor-positive (ER+) breast cancers, however, use of this strategy has been challenging because of the lack of validated surrogates of long-term efficacy and the overall good prognosis of the majority of patients with this cancer subtype. We review below the clinical benefits of neoadjuvant endocrine therapy for ER+/HER2-negative breast cancer, its use and limitations for drug development, prioritization of adjuvant and metastatic trials, and biomarker discovery.Significance: Neoadjuvant endocrine therapy is an excellent platform for the development of investigational drugs, triaging of novel combinations, biomarker validation, and discovery of mechanisms of drug resistance. This review summarizes the clinical and investigational benefits of this approach, with a focus on how to best integrate predictive biomarkers into novel clinical trial designs. Cancer Discov; 7(6); 561-74. ©2017 AACR.
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Affiliation(s)
- Angel L Guerrero-Zotano
- Departments of Medicine and Cancer Biology; Breast Cancer Program, Vanderbilt-Ingram Cancer Center; Vanderbilt University Medical Center, Nashville, Tennessee
| | - Carlos L Arteaga
- Departments of Medicine and Cancer Biology; Breast Cancer Program, Vanderbilt-Ingram Cancer Center; Vanderbilt University Medical Center, Nashville, Tennessee.
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Matsuda N, Lim B, Wang X, Ueno NT. Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer. Expert Opin Investig Drugs 2017; 26:463-479. [PMID: 28271910 PMCID: PMC5826640 DOI: 10.1080/13543784.2017.1299707] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 02/22/2017] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.
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Affiliation(s)
- Naoko Matsuda
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Bora Lim
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaoping Wang
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Naoto T. Ueno
- Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Augereau P, Patsouris A, Bourbouloux E, Gourmelon C, Abadie Lacourtoisie S, Berton Rigaud D, Soulié P, Frenel JS, Campone M. Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy. Ther Adv Med Oncol 2017; 9:335-346. [PMID: 28529550 PMCID: PMC5424863 DOI: 10.1177/1758834017693195] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2016] [Accepted: 01/16/2017] [Indexed: 11/17/2022] Open
Abstract
Endocrine therapy is the mainstay of treatment of estrogen-receptor-positive (ER+) breast cancer with an overall survival benefit. However, some adaptive mechanisms in the tumor emerge leading to the development of a resistance to this therapy. A better characterization of this process is needed to overcome this resistance and to develop new tailored therapies. Mechanisms of resistance to hormone therapy result in activation of transduction signal pathways, including the cell cycle regulation with cyclin D/CDK4/6/Rb pathway. The strategy of combined hormone therapy with targeted agents has shown an improvement of progression-free survival (PFS) in several phase II or III trials, including three different classes of drugs: mTOR inhibitors, PI3K and CDK4/6 inhibitors. A recent phase III trial has shown that fulvestrant combined with a CDK 4/6 inhibitor doubles PFS in aromatase inhibitor-pretreated postmenopausal ER+ breast cancer. Other combinations are ongoing to disrupt the interaction between PI3K/AKT/mTOR and cyclin D/CDK4/6/Rb pathways. Despite these successful strategies, reliable and reproducible biomarkers are needed. Tumor genomics are dynamic over time, and blood-based biomarkers such as circulating tumor DNA represent a major hope to elucidate the adaptive mechanisms of endocrine resistance. The optimal combinations and biomarkers to guide this strategy need to be determined.
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Affiliation(s)
- Paule Augereau
- Department of Medical Oncology, Institut cancerologie de l'ouest site Paul Papin, 15 rue Andre Bocquel 49055 Angers Cedex 02, France
| | - Anne Patsouris
- Department of Medical Oncology, Institut cancerologie de l'ouest site Paul Papin, France
| | - Emmanuelle Bourbouloux
- Department of Medical Oncology, Institut cancerologie de l'ouest site René Gauducheau, Saint Herblain, France
| | - Carole Gourmelon
- Department of Medical Oncology, Institut cancerologie de l'ouest site René Gauducheau, Saint Herblain, France
| | | | - Dominique Berton Rigaud
- Department of Medical Oncology, Institut cancerologie de l'ouest site René Gauducheau, Saint Herblain, France
| | - Patrick Soulié
- Department of Medical Oncology, Institut cancerologie de l'ouest site Paul Papin, France
| | - Jean Sebastien Frenel
- Department of Medical Oncology, Institut cancerologie de l'ouest site René Gauducheau, Saint Herblain, France
| | - Mario Campone
- Department of Medical Oncology, Institut cancerologie de l'ouest site Paul Papin, France Department of Medical Oncology, Institut cancerologie de l'ouest site René Gauducheau, Saint Herblain, France
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Keenen MM, Kim S. Tumor suppressor ING4 inhibits estrogen receptor activity in breast cancer cells. BREAST CANCER-TARGETS AND THERAPY 2016; 8:211-221. [PMID: 27895513 PMCID: PMC5117803 DOI: 10.2147/bctt.s119691] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Resistance to antiestrogen therapy remains a significant problem in breast cancer. Low expression of inhibitor of growth 4 (ING4) in primary tumors has been correlated with increased rates of recurrence in estrogen receptor-positive (ER+) breast cancer patients, suggesting a role for ING4 in ER signaling. This study provides evidence that ING4 inhibits ER activity. ING4 overexpression increased the sensitivity of T47D and MCF7 ER+ breast cancer cells to hormone deprivation. ING4 attenuated maximal estrogen-dependent cell growth without affecting the dose–response of estrogen. These results indicated that ING4 functions as a noncompetitive inhibitor of estrogen signaling and may inhibit estrogen-independent ER activity. Supportive of this, treatment with fulvestrant but not tamoxifen rendered T47D cells sensitive to hormone deprivation as did ING4 overexpression. ING4 did not affect nuclear ERα protein expression, but repressed selective ER-target gene transcription. Taken together, these results demonstrated that ING4 inhibited estrogen-independent ER activity, suggesting that ING4-low breast tumors recur faster due to estrogen-independent ER activity that renders tamoxifen less effective. This study puts forth fulvestrant as a proposed therapy choice for patients with ING4-low ER+ breast tumors.
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Affiliation(s)
- Madeline M Keenen
- Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ
| | - Suwon Kim
- Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ; Division of Cancer and Cell Biology, Translational Genomics Research Institute, Phoenix, AZ, USA
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Tryfonidis K, Zardavas D, Katzenellenbogen BS, Piccart M. Endocrine treatment in breast cancer: Cure, resistance and beyond. Cancer Treat Rev 2016; 50:68-81. [DOI: 10.1016/j.ctrv.2016.08.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2016] [Revised: 08/22/2016] [Accepted: 08/29/2016] [Indexed: 10/21/2022]
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Beith J, Burslem K, Bell R, Woodward N, McCarthy N, De Boer R, Loi S, Redfern A. Hormone receptor positive, HER2 negative metastatic breast cancer: A systematic review of the current treatment landscape. Asia Pac J Clin Oncol 2016; 12 Suppl 1:3-18. [PMID: 27001208 DOI: 10.1111/ajco.12491] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2016] [Indexed: 11/28/2022]
Abstract
Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10,000 patients, the greatest improvement in progression-free survival (PFS) was seen with the addition of a cyclin-dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy. Treatment with a mammalian target of rapamycin (mTOR) inhibitor, phosphoinositol-3-kinase (Pi3K) inhibitor, vascular endothelial growth factor (VEGF) inhibitor and with a selective estrogen receptor degrader (SERD) also showed benefit in PFS for selected trials. Overall survival (OS) improved with the use of mTOR inhibitors and a SERD; however, studies were not powered for an OS endpoint. Encouraging results from early studies of histone deacetylase (HDAC) and B-cell lymphoma (BCL2) inhibitors are yet to be confirmed in phase III clinical trials. Study discontinuation rates and toxicity-related deaths were highest with VEGF inhibitors in combination with endocrine therapy, limiting their use in hormone receptor positive breast cancer. CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line settings, but required additional monitoring for common toxicities. The activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was limited to the first-line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs. Overall, PFS benefit appears to be greatest when agents acting on CDK4/6, mTOR and Pi3K pathways, and SERDs are added to standard endocrine therapy. If these early results persist in further studies, these data are likely to change the way we treat hormone receptor positive, HER2 negative metastatic breast cancer. In the follow-up article to this review, we will consider the potential future treatment options for these patients.
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Affiliation(s)
- Jane Beith
- Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
| | - Katie Burslem
- Write Source Medical Pty Ltd, Sydney, New South Wales, Australia
| | - Richard Bell
- Deakin University, Warun Ponds, Victoria, Australia
| | - Natasha Woodward
- Mater Health Services/Mater Research Institute, South Brisbane, Queensland, Australia
| | - Nicole McCarthy
- Wesley Medical Centre and University of Queensland, Queensland, Australia
| | | | - Sherene Loi
- Peter MacCallum Cancer Centre, Victoria, Australia
| | - Andrew Redfern
- Fiona Stanley Hospital, Perth, Western Australia, Australia
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Sonnenblick A, Pondé N, Piccart M. Metastatic breast cancer: The Odyssey of personalization. Mol Oncol 2016; 10:1147-59. [PMID: 27430154 PMCID: PMC5423195 DOI: 10.1016/j.molonc.2016.07.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Revised: 06/27/2016] [Accepted: 07/05/2016] [Indexed: 12/31/2022] Open
Abstract
Metastatic breast cancer is the most frequent cause of cancer death for women worldwide. In the last 15 years, a large number of new agents have entered clinical use, a result of the dramatic increase in our understanding of the molecular underpinnings of metastatic breast cancer. However, while these agents have led to better outcomes, they are also at the root cause of increasing financial pressure on healthcare systems. Moreover, decision making in an era where every year new agents are added to the therapeutic armamentarium has also become a significant challenge for medical oncologists. In the present article, we will provide an ample review on the most recent developments in the field of treatment of the different subtypes of metastatic breast cancer with a critical discussion on the slow progress made in identifying response biomarkers. New hopes in the form of ctDNA monitoring and functional imaging will be presented.
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Affiliation(s)
- A Sonnenblick
- Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 125, B 1000 Brussels, Belgium; Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - N Pondé
- Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 125, B 1000 Brussels, Belgium
| | - M Piccart
- Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo 125, B 1000 Brussels, Belgium.
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Martinello R, Genta S, Galizia D, Geuna E, Milani A, Zucchini G, Valabrega G, Montemurro F. New and developing chemical pharmacotherapy for treating hormone receptor-positive/HER2-negative breast cancer. Expert Opin Pharmacother 2016; 17:2179-2189. [PMID: 27646965 DOI: 10.1080/14656566.2016.1236914] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Endocrine therapy is the mainstay of treatment for a substantial proportion of hormone receptor positive (HR+) breast cancer (BC). Indeed, patients with metastatic disease not immediately life threatening may experience long disease control across several lines of endocrine therapy. The major limitation of this therapeutic approach is primary or acquired resistance. A better understanding of endocrine resistance has resulted in newer targeted agents to be added to endocrine therapy. Areas covered: This review highlights new findings in the treatment of HR+/HER2- BC, with a particular focus on new drugs from phase 3 development onwards. Expert opinion: Combining endocrine therapy with agents targeting putative mechanisms of endocrine resistance is a newer treatment paradigm in HR+ BC. Adding a biologically targeted agent to endocrine therapy results in improved response rate, and clinical benefit rate, and prolonged progression-free survival. A clear advantage in overall survival has not yet been reported. Combination therapy allows to delay chemotherapy but increases toxicities and costs, which are critical factors in decision making in the clinical practice. Moreover, identification and validation of biomarkers of response are needed. Ongoing and future trials should elucidate the role of these compounds in the treatment of HR+/HER2- BC.
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Affiliation(s)
- Rossella Martinello
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
| | - Sofia Genta
- b Medical Oncology 1 , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy.,c Department of Oncology , University of Torino , Turin , Italy
| | - Danilo Galizia
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
| | - Elena Geuna
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
| | - Andrea Milani
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
| | - Giorgia Zucchini
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
| | - Giorgio Valabrega
- b Medical Oncology 1 , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy.,c Department of Oncology , University of Torino , Turin , Italy
| | - Filippo Montemurro
- a Investigative Clinical Oncology (INCO) , Candiolo Cancer Institute-FPO- IRCCS , Turin , Italy
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Johnston S, Basik M, Hegg R, Lausoontornsiri W, Grzeda L, Clemons M, Dreosti L, Mann H, Stuart M, Cristofanilli M. Inhibition of EGFR, HER2, and HER3 signaling with AZD8931 in combination with anastrozole as an anticancer approach: Phase II randomized study in women with endocrine-therapy-naïve advanced breast cancer. Breast Cancer Res Treat 2016; 160:91-99. [PMID: 27654971 DOI: 10.1007/s10549-016-3979-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2016] [Accepted: 09/06/2016] [Indexed: 11/29/2022]
Abstract
PURPOSE AZD8931 is an orally bioavailable, reversible tyrosine kinase inhibitor of EGFR, HER2, and HER3 signaling. The Phase II MINT study (ClinicalTrials.gov NCT01151215) investigated whether adding AZD8931 to endocrine therapy would delay development of endocrine resistance in patients with hormone-sensitive advanced breast cancer. METHODS Patients were randomized 1:1:1 to receive daily anastrozole (1 mg) in combination with AZD8931 20 mg twice daily (bid), AZD8931 40 mg bid, or placebo. The primary objective was evaluation of progression-free survival (PFS) in patients treated with combination AZD8931 and anastrozole versus anastrozole alone. Secondary objectives included assessment of safety and tolerability, objective response rate, and overall survival. RESULTS At the interim analysis, 359 patients were randomized and received anastrozole in combination with AZD8931 20 mg (n = 118), 40 mg (n = 120), or placebo (n = 121); 39 % of patients (n = 141) had a progression event. Median PFS (HR; 95 % CI vs placebo) in the AZD8931 20, 40 mg, and placebo arms was 10.9 (1.37; 0.91-2.06, P = 0.135), 13.8 (1.16; 0.77-1.75, P = 0.485), and 14.0 months, respectively. No indication of clinical benefit was observed following treatment with AZD8931 for the secondary endpoints. Safety findings showed a greater incidence of diarrhea (40, 51, and 12 % for AZD8931 20, 40 mg, and placebo, respectively), rash (32, 48, and 12 %), dry skin (19, 25, and 2 %), and acneiform dermatitis (16, 28, and 2 %) in patients treated with AZD8931 versus placebo. CONCLUSIONS AZD8931, in combination with endocrine therapy, does not appear to enhance endocrine responsiveness and is associated with greater skin and gastrointestinal toxicity.
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Affiliation(s)
- Stephen Johnston
- The Royal Marsden NHS Foundation Trust, The Royal Marsden Hospital, Fulham Road, Chelsea, London, SW3 6JJ, UK.
| | - Mark Basik
- Jewish General Hospital, Montreal, Canada
| | | | | | | | - Mark Clemons
- The Ottawa Hospital Cancer Center, Ottawa, Canada
| | - Lydia Dreosti
- University of Pretoria and Steve Biko Academic Hospital, Pretoria, South Africa
| | | | | | - Massimo Cristofanilli
- Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
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Gradishar WJ. Treatment challenges for community oncologists treating postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. Cancer Manag Res 2016; 8:85-94. [PMID: 27468248 PMCID: PMC4946864 DOI: 10.2147/cmar.s98249] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Community-based oncologists are faced with challenges and opportunities when delivering quality patient care, including high patient volumes and diminished resources; however, there may be the potential to deliver increased patient education and subsequently improve outcomes. This review discusses the treatment of postmenopausal women with endocrine-resistant, hormone receptor-positive, human epidermal growth factor receptor 2- negative advanced breast cancer in order to illustrate considerations in the provision of pertinent quality education in the treatment of these patients and the management of therapy-related adverse events. An overview of endocrine-resistant breast cancer and subsequent treatment challenges is also provided. Approved treatment options for endocrine-resistant breast cancer include hormonal therapies and mammalian target of rapamycin inhibitors. Compounds under clinical investigation are also discussed.
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Affiliation(s)
- William J Gradishar
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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48
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Goetz MP, Suman VJ. Window-of-Opportunity Trials in the Preoperative Setting: Insights Into Drug Development for Estrogen Receptor–Positive Breast Cancer. J Clin Oncol 2016; 34:1970-2. [DOI: 10.1200/jco.2015.66.2312] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
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Redfern A, Burslem K, Woodward N, Beith J, McCarthy N, De Boer R, Bell R. Hormone receptor positive, HER2 negative metastatic breast cancer: Future treatment landscape. Asia Pac J Clin Oncol 2016; 12 Suppl 1:19-31. [PMID: 27001209 DOI: 10.1111/ajco.12492] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/01/2016] [Indexed: 12/31/2022]
Abstract
Endocrine therapy is an established and effective treatment strategy for hormone receptor positive metastatic breast cancer. The clinical utility of endocrine therapy is lost over time due to evolving changes in tumor biology and the development of endocrine resistance. Many agents targeting the intracellular signaling pathways associated with endocrine resistance are in development. Encouraging early results have been seen for agents which directly target the estrogen receptor (ER), inhibitors of co-signaling pathways, inhibitors of ER chaperones, ER antagonists able to inhibit mutated or otherwise activated ERs, and modulators of histone acetylation restoring synthesis of ER signaling components. Following our systematic review of treatments with established benefits in this supplement, we review some of the more promising new strategies for overcoming endocrine resistance, looking at the impact on disease control and quality of life for women with hormone receptor positive, HER2 negative breast cancer. We also examine the biomarkers that may guide selection of the best therapy for the individual.
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Affiliation(s)
- Andrew Redfern
- Fiona Stanley Hospital, Perth, Western Australia, Australia
| | - Katie Burslem
- WriteSource Medical Pty Ltd, Sydney, New South Wales, Australia
| | - Natasha Woodward
- Mater Health Services/Mater Research Institute, South Brisbane, Queensland, Australia
| | - Jane Beith
- Chris O'Brien Lifehouse, Camperdown, New South Wales, Australia
| | - Nicole McCarthy
- Wesley Medical Centre, Auchenflower, and University of Queensland, Queensland, Australia
| | | | - Richard Bell
- Deakin University, Warun Ponds, Victoria, Australia
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50
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Malorni L, Giuliano M, Migliaccio I, Wang T, Creighton CJ, Lupien M, Fu X, Hilsenbeck SG, Healy N, De Angelis C, Mazumdar A, Trivedi MV, Massarweh S, Gutierrez C, De Placido S, Jeselsohn R, Brown M, Brown PH, Osborne CK, Schiff R. Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 2016; 14:470-81. [PMID: 26965145 DOI: 10.1158/1541-7786.mcr-15-0423] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2016] [Accepted: 02/20/2016] [Indexed: 01/02/2023]
Abstract
UNLABELLED The transcription factor AP-1 is downstream of growth factor (GF) receptors (GFRs) and stress-related kinases, both of which are implicated in breast cancer endocrine resistance. Previously, we have suggested that acquired endocrine resistance is associated with increased activity of AP-1 in an in vivo model. In this report, we provide direct evidence for the role of AP-1 in endocrine resistance. First, significant overlap was found between genes modulated in tamoxifen resistance and a gene signature associated with GF-induced estrogen receptor (ER) cistrome. Interestingly, these overlapping genes were enriched for key signaling components of GFRs and stress-related kinases and had AP-1 motifs in their promoters/enhancers. Second, to determine a more definitive role of AP-1 in endocrine resistance, AP-1 was inhibited using an inducible dominant-negative (DN) cJun expressed in MCF7 breast cancer cells in vitro and in vivo AP-1 blockade enhanced the antiproliferative effect of endocrine treatments in vitro, accelerated xenograft tumor response to tamoxifen and estrogen deprivation in vivo, promoted complete regression of tumors, and delayed the onset of tamoxifen resistance. Induction of DN-cJun after the development of tamoxifen resistance resulted in dramatic tumor shrinkage, accompanied by reduced proliferation and increased apoptosis. These data suggest that AP-1 is a key determinant of endocrine resistance by mediating a global shift in the ER transcriptional program. IMPLICATIONS AP-1 represents a viable therapeutic target to overcome endocrine resistance. Mol Cancer Res; 14(5); 470-81. ©2016 AACR.
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Affiliation(s)
- Luca Malorni
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Sandro Pitigliani Medical Oncology Unit and Translational Research Unit, Oncology Department, Hospital of Prato, Prato, Italy.
| | - Mario Giuliano
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy
| | - Ilenia Migliaccio
- Sandro Pitigliani Medical Oncology Unit and Translational Research Unit, Oncology Department, Hospital of Prato, Prato, Italy
| | - Tao Wang
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas
| | - Chad J Creighton
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Mathieu Lupien
- Ontario Cancer Institute, Princess Margaret Cancer Center-University Health Network, Ontario Institute for Cancer Research and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Xiaoyong Fu
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Susan G Hilsenbeck
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Nuala Healy
- Department of Radiology, St. James's Hospital, Dublin, Ireland
| | - Carmine De Angelis
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy
| | - Abhijit Mazumdar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Meghana V Trivedi
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Clinical Sciences and Administration, University of Houston College of Pharmacy, Houston, Texas
| | - Suleiman Massarweh
- Department of Medicine and Stanford Cancer Institute, Stanford University, Stanford, California
| | - Carolina Gutierrez
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Pathology, Baylor College of Medicine, Houston, Texas
| | - Sabino De Placido
- Department of Clinical Medicine and Surgery, Oncology Division, University of Naples Federico II, Naples, Italy
| | - Rinath Jeselsohn
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Myles Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Powel H Brown
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - C Kent Osborne
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Rachel Schiff
- Lester and Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas. Department of Medicine, Baylor College of Medicine, Houston, Texas. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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