Autophagy Differentially Regulates Distinct Breast Cancer Stem-like Cells in Murine Models via EGFR/Stat3 and Tgfβ/Smad Signaling

作者：Yeo, Syn Kok; Wen, Jian; Chen, Song; Guan, Jun-Lin^*

来源：Cancer Research, 2016, 76(11): 3397-3410.

DOI：10.1158/0008-5472.CAN-15-2946

• GROWTH
• MOUSE
• RESISTANCE
• IDENTIFICATION
• TUMORIGENESIS
• MAINTENANCE
• METASTASIS
• INHIBITION
• ACTIVATION
• TRANSITION

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 ALDH(+) and CD29(hi)CD61(+) markers, respectively, in murine models of breast cancer. While both BCSC exhibit enhanced tumor-initiating potential, CD29(hi)CD61(+) BCSC displayed increased invasive abilities and higher expression of epithelial-to-mesenchymal transition and mammary stem cell-associated genes, whereas ALDH(+) BCSC were more closely associated with luminal progenitors. Attenuating the autophagy regulator FIP200 diminished the tumor-initiating properties of both ALDH(+) and CD29(hi)CD61(+) BCSC, as achieved by impairing either the Stat3 or TGF beta/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgf beta-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.

• 出版日期2016-6-1