Tackhoon Kim1,2, Suk-Jin Yang3, Daehee Hwang1,2, Jinhoi Song4, Minchul Kim1,2, Sang Kyum Kim5, Keunsoo Kang1, Jaebum Ahn1,2, Daeyoup Lee1, Mi-young Kim1, Seyun Kim1, Ja Seung Koo5, Sang Seok Koh6, Seon-Young Kim3 & Dae-Sik Lim1
1 Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. 2 National Creative Research Center for Cell Division and Differentiation, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. 3 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea. 4 Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Korea. 5 Department of Pathology, Yonsei University College of Medicine, Seoul 120-752, Korea. 6 Department of Biological Sciences, Dong-A University, Busan 604-714, Korea.
Correspondence to : Dae-Sik Lim
The switch between stem/progenitor cell expansion and differentiation is critical for organ homeostasis. The mammalian Hippo pathway effector and oncoprotein YAP expands undifferentiated stem/progenitor cells in various tissues. However, the YAP-associated transcription factors and downstream targets underlying this stemness-promoting activity are poorly understood. Here we show that the SRF?IL6 axis is the critical mediator of YAP-induced stemness in mammary epithelial cells and breast cancer. Specifically, serum response factor (SRF)-mediated binding and recruitment of YAP to mammary stem cell (MaSC) signature-gene promoters induce numerous MaSC signature genes, among which the target interleukin (IL)-6 is critical for YAP-induced stemness. High SRF-YAP/TAZ expression is correlated with IL6-enriched MaSC/basal-like breast cancer (BLBC). Finally, we show that this high SRF expression enables YAP to more efficiently induce IL6 and stemness in BLBC compared with luminal-type breast cancer. Collectively, our results establish the importance of SRF-YAP-IL6 signalling in promoting MaSC-like properties in a BLBC-specific manner.