Abstract A27: Dissecting the functional landscape of triple-negative breast cancer

Abstract

Abstract Our group employed a pangenomic loss of function screening approach to systematically dissect the molecular architecture that functionally supports Triple Negative Breast Cancer (TNBC). Given that treatment options for this disease are typically limited to cytotoxic therapies, we applied a paclitaxel-based synthetic lethal approach to identify those molecular components that modulate chemoresponsiveness. To account for heterogeneity within the patient population, we screened 4 triple negative tumor-derived breast cancer cell lines that represent the spectrum of TNBC oncogenic aberrations and chemoresponse profiles. We also accounted for the two molecular subtypes, Claudin-Low and Basal-Like, that comprise the majority of TNBC cases. These screens revealed a number of core modulators of tumor cell viability and paclitaxel-induced cellular stress that have not been previously appreciated for supporting TNBC biology at the cell autonomous level. For example, this strategy implicated AMPK family member, SIK2, as a key nutrient sensor that may inhibit excessive autophagy. Inhibition of SIK2 leads to enhanced autophagic flux and a loss of cell viability in a variety of TNBC genetic backgrounds. In addition, we discovered the signaling supported by the cytokine receptor, CXCR3, and its ligand, CXCL9, to be repurposed to promote mitotic fidelity and thus, tumor cell fitness specifically in the Basal-Like TNBC molecular subtype. Finally, we uncovered a requirement for the transcription factor, ZNF165, in specifying the gene expression profiles activated by TGFβ signaling. In particular, the TGFβ target protein, SERPINE1, is required to promote prosurvival signaling in the Claudin-Low TNBC molecular subtype. Given that the expression of ZNF165 is otherwise restricted to the male testes, ZNF165 may represent a mechanism by which tumors engage anomaly-expressed proteins to promote survival. Taken together, we have uncovered novel tumor cell vulnerabilities in TNBC that could be therapeutically leveraged to enhance current therapeutic approaches. Citation Format: Kimberly Maxfield, Aleix Prat, Kathleen Corcoran, Angelique Whitehurst. Dissecting the functional landscape of triple-negative breast cancer. [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 A27.