Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells inMurineModels via EGFR/Stat3 and Tgfb/Smad Signaling

Cancer stem-like cells contribute to tumor heterogeneity and have been implicated in disease relapse and drug resistance. Here we show the coexistence of distinct breast cancer stem-like cells (BCSC) as identified by ALDHþ and CD29hiCD61þ markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29hiCD61þ BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell–associated genes, whereas ALDHþ BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumorinitiating properties of both ALDHþ and CD29hiCD61þ BCSC, as achieved by impairing either the Stat3 or TGFb/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgfb-R1 inhibitor LY-2157299 inhibited the formation of both epithelial and mesenchymal BCSC colonies. In vivo, this combination treatment was sufficient to limit tumor growth and reduce BCSC number. Overall, our findings reveal a differential dependence of heterogeneous BCSC populations on divergent signaling pathways, with implications on how to tailor drug combinations to improve therapeutic efficacy. Cancer Res; 76(11); 3397–410. 2016 AACR.