VAV3 mediates resistance to breast cancer endocrine therapy

Abstract

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.

Up-regulated LINC01234 promotes non-small-cell lung cancer cell metastasis by activating VAV3 and repressing BTG2 expression

“…The VAV family of guanine nucleotide exchange factors participates in numerous important pathological processes, including oncogenesis and cell transformation. Recent studies showed that VAV3 expression is increased in breast, prostate, and colorectal cancer [25][26][27], and VAV3 promoted cell metastasis in gastric cancer [28]. Consistent with this, we also found that VAV3 was upregulated in NSCLC, and its knockdown inhibited NSCLC cell invasion.…”

Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

“…AGR3 may serve as a biomarker in luminal breast cancer (Garczyk et al, 2015). The guanidine nucleotide exchange factor gene VAV3 was recently found to be involved in resistance to endocrine therapy in breast cancer (Aguilar et al, 2014). In addition to ESR1, AGR2 and AGR3 , the GREB1 and NR2F2 genes were identified as menin/FOXA1/GATA3 enhancer linked target genes.…”

Targeting Rac and Cdc42 GEFs in Metastatic Cancer

“…In breast cancer cells, Vav3 activated estrogen receptor (ER) α partially via PI3K-Akt signaling and promoted cell growth (Chen et al, 2015). However, Vav3 expression was higher in ER negative tissue, and high levels of nuclear Vav3 was associated with poorer endocrine therapy response (Aguilar et al, 2014). Similarly, in colorectal cancer, Vav3 expression was higher in malignant tissue compared to normal tissue, correlating with invasion and proliferation, and thus an advanced stage with poorer prognosis (Uen et al, 2015).…”