Breast cancer cells bearing similarities to normal mammary stem cells represent some of the most aggressive tumors cells. Here, we show that αvβ3/Slug+ “stem-like” tumor cells are highly vulnerable to cell death induced by PUMA (p53-upregulated modulator of apoptosis). In human breast cancers, we were surprised to find that αvβ3/Slug+ cells represent a unique subset of tumor cells associated with progression that are present in all major histological subtypes. Analysis of “stem-like” cell lines showed that αvβ3 directs an EMT-independent role for Slug in suppressing PUMA expression and promoting tumor cell survival and stemness. In fact, αvβ3 is both necessary and sufficient for PUMA suppression and PUMA knockdown specifically rescued defective colony formation and tumor initiation caused by decreased β3 expression. Inducing PUMA expression with specific therapies selectively ablated αvβ3/Slug+ cells, preventing the formation of new colonies or tumors, with no effect on established disease. These new findings define an unexpected role for αvβ3/Slug-mediated PUMA suppression in driving stemness and suggest that inducing PUMA with specific therapies can selectively target “stem-like” breast cancer cells to prevent aggressive disease.

Citation Format: Qi Sun, Jacqueline Lesperance, Jay S. Desgrosellier. PUMA expression targets αvβ3/Slug+ “stem-like” tumor cells to prevent breast cancer progression independent of subtype. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3321.