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

• Published in: Cancer research (Chicago, Ill.) Vol. 76; no. 11; pp. 3397 - 3410
• Main Authors: Yeo, Syn Kok, Wen, Jian, Chen, Song, Guan, Jun-Lin
• Format: Journal Article
• Language: English
• Published: United States 01.06.2016
• Subjects: 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; Female; Humans; Immunoenzyme Techniques; Mice; Neoplasm Invasiveness; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Real-Time Polymerase Chain Reaction; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Smad Proteins - genetics; Smad Proteins - metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - metabolism; Tumor Cells, Cultured
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-15-2946

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.