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- Title
VAV3 mediates resistance to breast cancer endocrine therapy.
- Authors
Aguilar, Helena; Urruticoechea, Ander; Halonen, Pasi; Kiyotani, Kazuma; Mushiroda, Taisei; Barril, Xavier; Serra-Musach, Jordi; Islam, Abul; Caizzi, Livia; Croce, Luciano Di; Nevedomskaya, Ekaterina; Zwart, Wilbert; Bostner, Josefine; Karlsson, Elin; Tenorio, Gizeh Pérez; Fornander, Tommy; Sgroi, Dennis C.; Garcia-Mata, Rafael; Jansen, Maurice P.H.M.; García, Nadia
- Abstract
Introduction 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. Here, we identify VAV3 as a critical component in this process. Methods A 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 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 the association with therapy 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. Results 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 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 response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 x 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. Conclusions This study proposes VAV3 as a biomarker and rationale signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.
- Subjects
BREAST cancer; HORMONE therapy; DNA microarrays; HUMAN genetic variation; GENE expression
- Publication
Breast Cancer Research, 2014, Vol 16, Issue 3, p1
- ISSN
1465-5411
- Publication type
Article
- DOI
10.1186/bcr3664