Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression

Cancer Res. 2015 Jun 1;75(11):2375-2386. doi: 10.1158/0008-5472.CAN-14-3076. Epub 2015 Apr 3.


Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / etiology
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Carcinogenesis / genetics
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Histocompatibility Antigens / genetics*
  • Histocompatibility Antigens / metabolism
  • Histone-Lysine N-Methyltransferase / genetics*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Humans
  • Leptin / genetics*
  • MCF-7 Cells
  • Mammary Neoplasms, Animal / genetics
  • Mammary Neoplasms, Animal / pathology
  • Mice
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Neoplastic Stem Cells / pathology
  • Obesity / complications
  • Obesity / genetics*
  • Obesity / pathology
  • Rats
  • Receptors, Leptin / genetics
  • STAT3 Transcription Factor / genetics*


  • Histocompatibility Antigens
  • Leptin
  • MIRN200 microRNA, human
  • MicroRNAs
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • EHMT2 protein, human
  • Histone-Lysine N-Methyltransferase