Abstract B25: Inhibition of autocrine signaling as a strategy to target tumor-initiating breast cancer cells

The epithelial-mesenchymal transition (EMT), a pleiotropic cellular program, has been associated with the acquisition of metastatic ability, self-renewal traits and resistance to chemotherapeutic drugs in breast cancer and other carcinomas. During normal development and tumor progression, this change in cell phenotype is induced by contextual signals that epithelial cells receive from their microenvironment, thereby promoting cellular heterogeneity. The signaling context responsible for inducing an EMT and maintaining the resulting cellular states has been unclear. We describe three signaling pathways, involving transforming growth factor (TGF)-beta and canonical/beta-catenin dependent and noncanonical Wnt signaling, that collaborate to induce activation of the EMT program and thereafter function in an autocrine fashion to maintain the resulting mesenchymal and stem cell-like state. Importantly, the induction of the EMT program and associated autocrine signaling is partly enabled by the downregulation of endogenous inhibitors of autocrine signals secreted by epithelial cells prior EMT, indicating a homeostatic mechanism. These inhibitors include secreted frizzled-related protein 1 (SFRP1), which has been shown by others to be a rate-limiting determinant of Wnt signaling, and Bone Morphogenetic Proteins, which appear to inhibit TGF-beta signaling. Conversely, disruption of autocrine signaling by adding back endogenous inhibitors of autocrine signaling as recombinant proteins inhibits migration and self-renewal of breast cancer cells in vitro and reduces tumorigenicity and spontaneous metastasis in vivo. Together, our results indicate that ongoing autocrine signaling is required for the maintenance of mesenchymal and stem cell traits in breast cancer cells. In the longer term, we intent to develop a cocktail small-molecule inhibitors to therapeutically interrupt multiple autocrine pathways, thereby forcing tumor-initiating cells of breast and other carcinomas to exit the mesenchymal, stem cell-like state. Since this cellular state is associated with resistance to chemotherapeutic drugs, we predict that such a treatment protocol might render breast cancer cells that have passed through an EMT more sensitive to standard chemotherapy, thereby serving as a therapeutic strategy to overcome tumor heterogeneity and relapse. Citation Format: Christina Scheel, Diana Dragoi, Elinor Ng Eaton, Sophia Hsin-Jung Li, Ferenc Reinhardt, Robert A. Weinberg. Inhibition of autocrine signaling as a strategy to target tumor-initiating breast cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Synthetic Lethal Approaches to Cancer Vulnerabilities; May 17-20, 2013; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(5 Suppl):Abstract nr B25.