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Endocrine resistance and breast cancer plasticity are controlled by CoREST.

ABSTRACT: Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER⁺ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.

SUBMITTER: Garcia-Martinez L

PROVIDER: S-EPMC9707522 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Endocrine resistance and breast cancer plasticity are controlled by CoREST.

Garcia-Martinez Liliana L Adams Andrew M AM Chan Ho Lam HL Nakata Yuichiro Y Weich Natalia N Stransky Stephanie S Zhang Zhao Z Alshalalfa Mohamed M Sarria Leonor L Mahal Brandon A BA Kesmodel Susan B SB Celià-Terrassa Toni T Liu Zhijie Z Minucci Saverio S Bilbao Daniel D Sidoli Simone S Verdun Ramiro E RE Morey Lluis L

Nature structural & molecular biology 20221107 11

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER<sup>+</sup> breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ERα and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN bin ...[more]

PMID: 36344844

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Project description:Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor ? (ER?) are among the most effective systemic treatments for ER?-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ER? transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ER? was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression.The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ER?. VAV3 was selectively reduced upon exposure to YC-1 or ER? depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value?=?8.4?×?10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy.This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

Project description:Approximately one-third of endocrine-treated women with estrogen receptor alpha-positive (ER+) breast cancers are at risk of recurrence due to intrinsic or acquired resistance. Thus, it is vital to understand the mechanisms underlying endocrine therapy resistance in ER+ breast cancer to improve patient treatment. Mitochondrial fatty acid β-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative breast cancer (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER+ breast cancer as a mechanism of resistance to endocrine therapy. A metabolically relevant, integrated gene signature was derived from transcriptomic, metabolomic, and lipidomic analyses in TNBC cells following inhibition of the FAO rate-limiting enzyme carnitine palmitoyl transferase 1 (CPT1), and this TNBC-derived signature was significantly associated with endocrine resistance in patients with ER+ breast cancer. Molecular, genetic, and metabolomic experiments identified activation of AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in endocrine-resistant ER+ breast cancer. CPT1 knockdown or treatment with FAO inhibitors in vitro and in vivo significantly enhanced the response of ER+ breast cancer cells to endocrine therapy. Consistent with the previous findings in TNBC, endocrine therapy-induced FAO activated the Src pathway in ER+ breast cancer. Src inhibitors suppressed the growth of endocrine-resistant tumors, and the efficacy could be further enhanced by metabolic priming with CPT1 inhibition. Collectively, this study developed and applied a TNBC-derived signature to reveal that metabolic reprogramming to FAO activates the Src pathway to drive endocrine resistance in ER+ breast cancer.SignificanceIncreased fatty acid oxidation induced by endocrine therapy activates Src signaling to promote endocrine resistance in breast cancer, which can be overcome using clinically approved therapies targeting FAO and Src.

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Endocrine resistance and breast cancer plasticity are controlled by CoREST.

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Endocrine resistance and breast cancer plasticity are controlled by CoREST.

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