@article {657,
	title = {VAV3 mediates resistance to breast cancer endocrine therapy.},
	journal = {Breast cancer research : BCR},
	volume = {16},
	year = {2014},
	month = {2014/05//},
	pages = {R53 - R53},
	abstract = {INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor alpha (ERalpha) are among the most effective systemic treatments for ERalpha-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERalpha 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 ERalpha 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 ERalpha. VAV3 was selectively reduced upon exposure to YC-1 or ERalpha 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.},
	url = {http://www.ncbi.nlm.nih.gov/pubmed/24886537},
	author = {Aguilar, Helena and Urruticoechea, Ander and Halonen, Pasi and Kiyotani, Kazuma and Mushiroda, Taisei and Barril, Xavier and Serra-Musach, Jordi and Islam, Abul and Caizzi, Livia and Di Croce, Luciano and Nevedomskaya, Ekaterina and Zwart, Wilbert and Bostner, Josefine and Karlsson, Elin and Tenorio, Gizeh P{\'e}rez and Fornander, Tommy and Sgroi, Dennis C and Garcia-Mata, Rafael and Jansen, Maurice Phm and Garc{\'\i}a, Nadia and Bonifaci, N{\'u}ria and Climent, Fina and Soler, Mar{\'\i}a Teresa and Rodr{\'\i}guez-Vida, Alejo and Gil, Miguel and Brunet, Joan and Martrat, Griselda and G{\'o}mez-Bald{\'o}, Laia and Extremera, Ana I and Figueras, Agnes and Balart, Josep and Clarke, Robert and Burnstein, Kerry L and Carlson, Kathryn E and Katzenellenbogen, John a and Vizoso, Miguel and Esteller, Manel and Villanueva, Alberto and Rodr{\'\i}guez-Pe{\~n}a, Ana B and Bustelo, Xos{\'e} R and Nakamura, Yusuke and Zembutsu, Hitoshi and St{\r a}l, Olle and Beijersbergen, Roderick L and Pujana, Miguel Angel}
}
