A basal-like breast cancer-specific role for SRF-IL6 in YAP-induced cancer stemness

Nat Commun. 2015 Dec 16;6:10186. doi: 10.1038/ncomms10186.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Breast Neoplasms / metabolism*
  • Cell Line, Tumor
  • Epithelial Cells / metabolism*
  • Female
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • Interleukin-6 / metabolism*
  • MCF-7 Cells
  • Mammary Glands, Human / cytology
  • Mammary Glands, Human / metabolism*
  • Mice
  • Mice, Nude
  • Microarray Analysis
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism*
  • Phosphoproteins / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Serum Response Factor / metabolism*
  • Stem Cells / metabolism
  • Tissue Array Analysis
  • Transcription Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • IL6 protein, human
  • Interleukin-6
  • Phosphoproteins
  • SRF protein, human
  • Serum Response Factor
  • Transcription Factors
  • YAP1 protein, human