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

Authors: Yeo, Syn Kok; Wen, Jian; Chen, Song; Guan, Jun-Lin

Published In Cancer Res, (2016 Jun 01)

Abstract: 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 TGFβ/Smad pathways, respectively. Furthermore, combining the Stat3 inhibitor Stattic and the Tgfβ-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.

PubMed ID: 27197172

MeSH Terms: Animals; Apoptosis; Autophagy*; Biomarkers, Tumor/genetics; Biomarkers, Tumor/metabolism; Blotting, Western; Breast Neoplasms/genetics; Breast Neoplasms/metabolism; Breast Neoplasms/pathology*; Cell Movement; Cell Proliferation; Disease Models, Animal; Epithelial-Mesenchymal Transition; ErbB Receptors/genetics; ErbB Receptors/metabolism*; Female; Humans; Immunoenzyme Techniques; Mice; Neoplasm Invasiveness; Neoplastic Stem Cells/metabolism; Neoplastic Stem Cells/pathology*; RNA, Messenger/genetics; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor/genetics; STAT3 Transcription Factor/metabolism*; Smad Proteins/genetics; Smad Proteins/metabolism*; Transforming Growth Factor beta/genetics; Transforming Growth Factor beta/metabolism*; Tumor Cells, Cultured