VAV3 mediates resistance to breast cancer endocrine therapy
Creators: name: Figueras, Agnes
name: Stål, Olle
name: Gil, Miguel
name: Gómez-Baldó, Laia
name: Bustelo, Xosé R.
name: Barril, Xavier
name: Pérez Tenorio, Gizeh
name: Aguilar, Helena
name: Caizzi, Livia
name: Jansen, Maurice P.H.M.
name: Zembutsu, Hitoshi
name: Beijersbergen, Roderick L.
name: Rodríguez-Vida, Alejo
name: Villanueva, Alberto
name: Burnstein, Kerry L.
name: García, Nadia
name: Rodríguez-Peña, Ana B.
name: Nevedomskaya, Ekaterina
name: Halonen, Pasi
name: Sgroi, Dennis C.
name: Serra-Musach, Jordi
name: Brunet, Joan
name: Extremera, Ana I.
name: Pujana, Miguel A.
name: Soler, María T.
name: Mushiroda, Taisei
name: Martrat, Griselda
name: Karlsson, Elin
name: Fornander, Tommy
name: Balart, Josep
name: Islam, Abul
name: Carlson, Kathryn E.
name: Bostner, Josefine
name: Nakamura, Yusuke
name: Clarke, Robert
name: Katzenellenbogen, John A.
name: Vizoso, Miguel
name: Urruticoechea, Ander
name: Bonifaci, Núria
name: Kiyotani, Kazuma
name: Di Croce, Luciano
name: Zwart, Wilbert
name: Climent, Fina
name: Esteller, Manel
name: Garcia-Mata, Rafael
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2014

description: IntroductionEndocrine 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.MethodsA cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα 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.ResultsThe 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 ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα 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.ConclusionsThis 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.