The Emerging Role of Extracellular Vesicles in Endocrine Resistant Breast Cancer

Breast cancer is the most common solid malignancy diagnosed in females worldwide, and approximately 70% of these tumors express estrogen receptor α (ERα), the main biomarker of endocrine therapy. Unfortunately, despite the use of long-term anti-hormone adjuvant treatment, which has significantly reduced patient mortality, resistance to the endocrine treatments often develops, leading to disease recurrence and limiting clinical benefits. Emerging evidence indicates that extracellular vesicles (EVs), nanosized particles that are released by all cell types and responsible for local and systemic intercellular communications, might represent a newly identified mechanism underlying endocrine resistance. Unraveling the role of EVs, released by transformed cells during the tumor evolution under endocrine therapy, is still an open question in the cancer research area and the molecular mechanisms involved should be better defined to discover alternative therapeutic approaches to overcome resistance. In this review, we will provide an overview of recent findings on the involvement of EVs in sustaining hormonal resistance in breast cancer and discuss opportunities for their potential use as biomarkers to monitor the therapeutic response and disease progression.

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FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1612835113 ◽

2016 ◽

Vol 113 (43) ◽

pp. E6600-E6609 ◽

Cited By ~ 61

Author(s):

Xiaoyong Fu ◽

Rinath Jeselsohn ◽

Resel Pereira ◽

Emporia F. Hollingsworth ◽

Chad J. Creighton ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Resistance ◽

Cancer Cell Line ◽

Estrogen Receptor Α ◽

Resistant Cell ◽

Transcriptional Reprogramming ◽

Er Positive ◽

Integrated Omics ◽

And Function

Forkhead box protein A1 (FOXA1) is a pioneer factor of estrogen receptor α (ER)–chromatin binding and function, yet its aberration in endocrine-resistant (Endo-R) breast cancer is unknown. Here, we report preclinical evidence for a role of FOXA1 in Endo-R breast cancer as well as evidence for its clinical significance. FOXA1 is gene-amplified and/or overexpressed in Endo-R derivatives of several breast cancer cell line models. Induced FOXA1 triggers oncogenic gene signatures and proteomic profiles highly associated with endocrine resistance. Integrated omics data reveal IL8 as one of the most perturbed genes regulated by FOXA1 and ER transcriptional reprogramming in Endo-R cells. IL-8 knockdown inhibits tamoxifen-resistant cell growth and invasion and partially attenuates the effect of overexpressed FOXA1. Our study highlights a role of FOXA1 via IL-8 signaling as a potential therapeutic target in FOXA1-overexpressing ER-positive tumors.

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Nuclear Mechanisms Involved in Endocrine Resistance

Frontiers in Oncology ◽

10.3389/fonc.2021.736597 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jürgen Dittmer

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Standard Treatment ◽

Current Knowledge ◽

Endocrine Resistance ◽

Estrogen Receptor Α ◽

Cyclin Dependent Kinase ◽

Druggable Targets ◽

Positive Breast Cancer

Endocrine therapy is a standard treatment offered to patients with ERα (estrogen receptor α)-positive breast cancer. In endocrine therapy, ERα is either directly targeted by anti-estrogens or indirectly by aromatase inhibitors which cause estrogen deficiency. Resistance to these drugs (endocrine resistance) compromises the efficiency of this treatment and requires additional measures. Endocrine resistance is often caused by deregulation of the PI3K/AKT/mTOR pathway and/or cyclin-dependent kinase 4 and 6 activities allowing inhibitors of these factors to be used clinically to counteract endocrine resistance. The nuclear mechanisms involved in endocrine resistance are beginning to emerge. Exploring these mechanisms may reveal additional druggable targets, which could help to further improve patients’ outcome in an endocrine resistance setting. This review intends to summarize our current knowledge on the nuclear mechanisms linked to endocrine resistance.

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Phase II study of the multikinase inhibitor dovitinib (TKI258) or placebo in combination with fulvestrant in postmenopausal, endocrine resistant HER2-/HR+ breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.tps1148 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. TPS1148-TPS1148

Author(s):

Fabrice Andre ◽

Richard Greil ◽

Neelima Denduluri ◽

Alejandro Javier Yovine ◽

Cathy Reddick ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Phase Ii ◽

Molecular Mechanisms ◽

Locally Advanced ◽

Endocrine Resistance ◽

Metastatic Breast ◽

Predictive Biomarkers ◽

Her2 Breast Cancer ◽

Patient Reported

TPS1148 Background: Overcoming endocrine resistance is a critical goal in the treatment of hormone receptor−positive (HR+) breast cancer. Molecular mechanisms associated with endocrine resistance include adaptive “cross-talk” between the estrogen receptor and the fibroblast growth factor receptor (FGFR). Up to 8% of HR+/HER2- breast cancer patients (pts) have amplification of the FGFR1 gene, which is associated with resistance to endocrine therapy but can be overcome via FGFR1 inhibition in preclinical models. Dovitinib is a potent FGF, VEGF, and PDGF receptor tyrosine kinase inhibitor that demonstrated antitumor activity in heavily pretreated breast cancer pts with FGF pathway amplification (FGFR1, FGFR2, or ligand FGF3; Andre et al, ASCO 2011). Dovitinib may reverse resistance to endocrine therapy related to FGF-pathway amplification and is studied here to determine if it can improve outcomes when combined with fulvestrant. Methods: Postmenopausal HER2-/HR+ locally advanced or metastatic breast cancer pts (N»150) progressing within 12 months of completion of adjuvant endocrine therapy or after ≤ 1 prior endocrine therapy in the advanced setting will be enrolled in this multicenter, randomized, double blind, placebo controlled, phase II trial. Pts will prospectively undergo molecular screening to enrich for FGF-amplification (FGFR1, FGFR2, or FGF3 amplification by qPCR; 45 amplified and 30 non-amplified pts per arm). Pts will be randomized 1:1 to receive fulvestrant (500 mg q4w [with an additional dose 2 wks after the initial dose]) in combination with oral dovitinib (500 mg, 5 days on/2 days off) or placebo until disease progression, unacceptable toxicity, or death. The primary endpoint is progression-free survival, with tumor assessments performed q8w. Secondary endpoints include overall response rate per RECIST v1.1, duration of response, overall survival, ECOG performance status and patient reported outcome scores over time, and safety. The pharmacodynamic effect of dovitinib on FGFR-associated angiogenic pathways in tumor specimens and potential predictive biomarkers of response to dovitinib will be explored.

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Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance

10.1101/2020.06.26.149948 ◽

2020 ◽

Author(s):

Li Li ◽

Ling Lin ◽

Jamunarani Veeraraghavan ◽

Yiheng Hu ◽

Xian Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Endocrine Therapy ◽

Breast Cancer Cells ◽

Endocrine Resistance ◽

Akt Signaling ◽

Bimolecular Fluorescence Complementation ◽

Clonogenic Assays

AbstractBackgroundEndocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance have not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized.MethodsThe endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays.ResultsOur results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib.ConclusionESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.

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Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer

Frontiers in Endocrinology ◽

10.3389/fendo.2021.599586 ◽

2021 ◽

Vol 12 ◽

Author(s):

Esmael Besufikad Belachew ◽

Dareskedar Tsehay Sewasew

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Molecular Mechanisms ◽

De Novo ◽

Endocrine Resistance ◽

Therapeutic Modality ◽

Breast Cancers ◽

Estrogen Receptor Positive ◽

Positive Breast Cancer

The estrogen receptor is a vital receptor for therapeutic targets in estrogen receptor-positive breast cancer. The main strategy for the treatment of estrogen receptor-positive breast cancers is blocking the estrogen action on estrogen receptors by endocrine therapy but this can be restricted via endocrine resistance. Endocrine resistance occurs due to both de novo and acquired resistance. This review focuses on the mechanisms of the ligand-dependent and ligand-independent pathways and other coregulators, which are responsible for endocrine resistance. It concludes that combinatorial drugs that target different signaling pathways and coregulatory proteins together with endocrine therapy could be a novel therapeutic modality to stop endocrine resistance.

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CDK4/6 Inhibitor Treatments in Patients with Hormone Receptor Positive, Her2 Negative Advanced Breast Cancer: Potential Molecular Mechanisms, Clinical Implications and Future Perspectives

Cancers ◽

10.3390/cancers13020332 ◽

2021 ◽

Vol 13 (2) ◽

pp. 332

Author(s):

Michela Roberto ◽

Antonio Astone ◽

Andrea Botticelli ◽

Luisa Carbognin ◽

Alessandra Cassano ◽

...

Keyword(s):

Breast Cancer ◽

Advanced Breast Cancer ◽

Hormone Receptor ◽

Molecular Mechanisms ◽

Breast Cancer Subtype ◽

Endocrine Resistance ◽

Growth Factor Receptor ◽

Predictive Biomarkers ◽

Disease Recurrence ◽

Advanced Breast

Hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is the most common breast cancer subtype, and endocrine therapy (ET) remains its therapeutic backbone. Although anti-estrogen therapies are usually effective initially, approximately 50% of HR+ patients develop resistance to ET within their lifetime, ultimately leading to disease recurrence and limited clinical benefit. The recent addition of cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors (palbociclib, ribociclib, abemaciclib) to ET have remarkably improved the outcome of patients with HR+ advanced breast cancer (ABC) compared with anti-estrogens alone, by targeting the cell-cycle machinery and overcoming some aspects of endocrine resistance. However, which patients are the better candidates for these drugs, which are the main characteristics for a better selection of patients or if there are predictive biomarkers of response, is still unknown. In this review we reported the mechanism of action of CDK4/6 inhibitors as well as their potential mechanism of resistance, their implications in clinical practice and the forthcoming strategies to enhance their efficacy in improving survival and quality of life of patients affected with HR+, HER2−, ABC.

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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

npj Breast Cancer ◽

10.1038/s41523-020-00210-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sanne Løkkegaard ◽

Daniel Elias ◽

Carla L. Alves ◽

Martin V. Bennetzen ◽

Anne-Vibeke Lænkholm ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Patients ◽

Endocrine Therapy ◽

Endocrine Resistance ◽

Predictive Marker ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Minichromosome Maintenance ◽

Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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Regulatory Interplay between miR-181a-5p and Estrogen Receptor Signaling Cascade in Breast Cancer

Cancers ◽

10.3390/cancers13030543 ◽

2021 ◽

Vol 13 (3) ◽

pp. 543

Author(s):

Rosaria Benedetti ◽

Chiara Papulino ◽

Giulia Sgueglia ◽

Ugo Chianese ◽

Tommaso De Marchi ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Mirna Expression ◽

Estrogen Receptor Alpha ◽

Estrogen Signaling ◽

Integrated Analysis ◽

Tumor Resistance ◽

Estrogen Receptor Signaling

The efficacy and side effects of endocrine therapy in breast cancer (BC) depend largely on estrogen receptor alpha (ERα) expression, the specific drug administered, and treatment scheduling. Although the benefits of endocrine therapy outweigh any adverse effects in the initial stages of BC, later- or advanced-stage tumors acquire resistance to treatments. The mechanisms underlying tumor resistance to therapy are still not well understood, posing a major challenge for BC patient care. Epigenetic regulation and miRNA expression may be involved in the switch from a treatment-sensitive to a treatment-resistant state and could provide a valid therapeutic strategy for ERα negative BC. Here, a hybrid lysine-specific histone demethylase inhibitor, MC3324, displaying selective estrogen receptor down-regulator-like activities in BC, was used to highlight the interplay between epigenetic and ERα signaling. MC3324 anticancer action is mediated by microRNA (miRNA) expression regulation, indicating an innovative function for this molecule. Integrated analysis suggests a crosstalk between estrogen signaling, ERα interactors, miRNAs, and their putative targets. Specifically, miR-181a-5p expression is regulated by MC3324 and has an impact on cellular levels of ERα. A comparison of breast tumor versus healthy mammary tissues confirmed the important role of miR-181a-5p in ERα regulation and points to its putative predictive function in BC therapy.

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Identification and Roles of miR-29b-1-3p and miR29a-3p-Regulated and Non-Regulated lncRNAs in Endocrine-Sensitive and Resistant Breast Cancer Cells

Cancers ◽

10.3390/cancers13143530 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3530

Author(s):

Penn Muluhngwi ◽

Carolyn M. Klinge

Keyword(s):

Breast Cancer ◽

Cancer Survival ◽

Expression Patterns ◽

Endocrine Resistance ◽

Estrogen Receptor Α ◽

Resistant Cell ◽

Differentially Expressed ◽

Primary Tumors ◽

Non Coding Rnas ◽

Mcf 7

Despite improvements in the treatment of endocrine-resistant metastatic disease using combination therapies in patients with estrogen receptor α (ERα) primary tumors, the mechanisms underlying endocrine resistance remain to be elucidated. Non-coding RNAs (ncRNAs), including microRNAs (miRNA) and long non-coding RNAs (lncRNA), are targets and regulators of cell signaling pathways and their exosomal transport may contribute to metastasis. Previous studies have shown that a low expression of miR-29a-3p and miR-29b-3p is associated with lower overall breast cancer survival before 150 mos. Transient, modest overexpression of miR-29b1-3p or miR-29a-3p inhibited MCF-7 tamoxifen-sensitive and LCC9 tamoxifen-resistant cell proliferation. Here, we identify miR-29b-1/a-regulated and non-regulated differentially expressed lncRNAs in MCF-7 and LCC9 cells using next-generation RNA seq. More lncRNAs were miR-29b-1/a-regulated in LCC9 cells than in MCF-7 cells, including DANCR, GAS5, DSCAM-AS1, SNHG5, and CRND. We examined the roles of miR-29-regulated and differentially expressed lncRNAs in endocrine-resistant breast cancer, including putative and proven targets and expression patterns in survival analysis using the KM Plotter and TCGA databases. This study provides new insights into lncRNAs in endocrine-resistant breast cancer.

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The Modern Landscape of Endocrine Therapy for Premenopausal Women with Breast Cancer

Breast Care ◽

10.1159/000439462 ◽

2015 ◽

Vol 10 (5) ◽

pp. 312-315 ◽

Cited By ~ 8

Author(s):

Lorenzo Rossi ◽

Olivia Pagani

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Ovarian Function ◽

Treatment Options ◽

Endocrine Resistance ◽

Premenopausal Women ◽

New Drugs ◽

Fine Tuning ◽

Individual Risk ◽

Ovarian Function Suppression

The optimal endocrine therapy for premenopausal women with early and advanced breast cancer still remains an important and controversial issue. For over 30 years, tamoxifen has been the gold standard in the adjuvant setting. New therapeutic options, such as the addition of ovarian function suppression to oral endocrine therapy (either tamoxifen or aromatase inhibitors), can improve outcomes over tamoxifen alone in well-selected patients. Treatment duration has also been revisited, and extended therapy is becoming a new standard of care, especially in high-risk patients. Endocrine therapy for advanced disease still represents a challenge and a research priority. New drugs and combinations able to overcome endocrine resistance are at the horizon, and their role in premenopausal women should be better elucidated. Side effects and quality of life (including family planning considerations) play an important role in treatment selection and in the patients' treatment adherence and should always be discussed before start of treatment. The paper will specifically focus on how to integrate all new treatment options in the current armamentarium of endocrine therapy of premenopausal women, with the aim of best fine-tuning treatment selections according to the individual risk/benefit evaluation.

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