Abstract 542: TGF-β inhibitors enhance chemotherapeutic efficacy via abrogation of autocrine and paracrine signaling in a triple negative breast cancer model

Triple negative breast cancer (TNBC) accounts for approximately 15-20% of total invasive breast cancers. This subtype of cancer is often correlated with poor prognosis, visceral metastases and relapse. Molecular characterization reveals that these tumors are negative for hormone receptors and they often develop chemo resistance. Tumor microenvironment, among other factors, has emerged as a definite player in the progression of breast cancer and may also confer chemo resistance. In the current study, we demonstrate that MDA-MB-231 cells show greater resistance to paclitaxel in heterotypic culture with RMF/EG-hTERT (reduction mammary fibroblast with enhanced GFP) as compared to homotypic culture. Further, we show that RMF/EG-hTERT cells can enhance the motility of MDA-MB-231 cells in trans well migration assays, which could be attenuated by the TGF-β inhibitor sRIII (soluble receptor type III). TGF-β signaling was shown to activate pro-survival pathways like PI3K/Akt and MAPK/ERK pathways in mammary fibroblasts suggesting that they may mediate the paracrine tumor-promoting activity of TGF-β. Autocrine TGF-β signaling has been shown to promote EMT and cancer stem cell-like features in TNBC cells and appears to be a potential therapeutic target. We show that paclitaxel in combination with sRIII was more effective in inhibiting the growth of MDA-MB-231 cells than either agent alone. The combination of a TGF-β inhibitor with paclitaxel was also more effective in inhibiting tumor sphere formation than either agent alone. Our future research will be focused on the mechanisms of autocrine and paracrine TGF-β signaling in mediating chemo resistance and the tumor-promoting activity of mammary stromal cells. Our research will reveal the potential use of TGF-β inhibitors as novel therapeutics in combination with chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 542. doi:10.1158/1538-7445.AM2011-542