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VAV3 mediates resistance to breast cancer endocrine therapy.

ABSTRACT: 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.

SUBMITTER: Aguilar H

PROVIDER: S-EPMC4076632 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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VAV3 mediates resistance to breast cancer endocrine therapy.

Aguilar Helena H Urruticoechea Ander A Halonen Pasi P Kiyotani Kazuma K Mushiroda Taisei T Barril Xavier X Serra-Musach Jordi J Islam Abul A Caizzi Livia L Di Croce Luciano L Nevedomskaya Ekaterina E Zwart Wilbert W Bostner Josefine J Karlsson Elin E Pérez Tenorio Gizeh G Fornander Tommy T Sgroi Dennis C DC Garcia-Mata Rafael R Jansen Maurice P H M MP García Nadia N Bonifaci Núria N Climent Fina F Soler María Teresa MT Rodríguez-Vida Alejo A Gil Miguel M Brunet Joan J Martrat Griselda G Gómez-Baldó Laia L Extremera Ana I AI Figueras Agnes A Balart Josep J Clarke Robert R Burnstein Kerry L KL Carlson Kathryn E KE Katzenellenbogen John A JA Vizoso Miguel M Esteller Manel M Villanueva Alberto A Rodríguez-Peña Ana B AB Bustelo Xosé R XR Nakamura Yusuke Y Zembutsu Hitoshi H Stål Olle O Beijersbergen Roderick L RL Pujana Miguel Angel MA

Breast cancer research : BCR 20140528 3

<h4>Introduction</h4>Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process.<h4>Methods</h4>A cell-based chemical compound screen was carried out to identi ...[more]

PMID: 24886537

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Project description:BackgroundMethyltransferase SETDB1 is highly expressed in breast cancer (BC), however, the mechanisms by which SETDB1 promotes BC progression to endocrine therapy resistance remains elusive. In this study, we examined the mechanisms by which SETDB1 contribute to BC endocrine therapy resistance.MethodsWe utilized therapy sensitive (MCF7 and ZR75), therapy resistant (MCF7-TamR, MCF7-FR, MCF7-PELP1cyto, MCF7-SETDB1) estrogen receptor alpha positive (ER+)BC models and conducted in vitro cell viability, colony formation, 3-dimensional cell growth assays to investigate the role of SETDB1 in endocrine resistance. RNA-seq of parental and SETDB1 knock down ER+ BC cells was used to identify unique pathways. SETDB1 interaction with PELP1 was identified by yeast-two hybrid screen and confirmed by immunoprecipitation and GST-pull down assays. Mechanistic studies were conducted using Western blotting, reporter gene assays, RT-qPCR, and in vitro methylation assays. Xenograft assays were used to establish the role of PELP1 in SETDB1 mediated BC progression.ResultsRNA-seq analyses showed that SETDB1 regulates expression of a subset of estrogen receptor (ER) and Akt target genes that contribute to endocrine therapy resistance. Importantly, using yeast-two hybrid screen, we identified ER coregulator PELP1 as a novel interacting protein of SETDB1. Biochemical analyses confirmed SETDB1 and PELP1 interactions in multiple BC cells. Mechanistic studies confirmed that PELP1 is necessary for SETDB1 mediated Akt methylation and phosphorylation. Further, SETDB1 overexpression promotes tamoxifen resistance in BC cells, and PELP1 knockdown abolished these effects. Using xenograft model, we provided genetic evidence that PELP1 is essential for SETDB1 mediated BC progression in vivo. Analyses of TCGA datasets revealed SETDB1 expression is positively correlated with PELP1 expression in ER+ BC patients.ConclusionsThis study suggests that the PELP1/SETDB1 axis play an important role in aberrant Akt activation and serves as a novel target for treating endocrine therapy resistance in breast cancer.

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VAV3 mediates resistance to breast cancer endocrine therapy.

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VAV3 mediates resistance to breast cancer endocrine therapy.

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