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

Cancer research (2015-04-05)
Chao-Ching Chang, Meng-Ju Wu, Jer-Yen Yang, Ignacio G Camarillo, Chun-Ju Chang
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Hydrocortisone, BioReagent, suitable for cell culture
Sigma-Aldrich
Hydrocortisone, ≥98% (HPLC)
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Hydrocortisone, γ-irradiated, powder, BioXtra, suitable for cell culture
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Leptin from mouse, ≥98% (SDS-PAGE), recombinant, expressed in E. coli, lyophilized powder
Sigma-Aldrich
Leptin human, ≥97% (SDS-PAGE), recombinant, expressed in E. coli, lyophilized powder
Sigma-Aldrich
Hydrocortisone, meets USP testing specifications
Sigma-Aldrich
S3I-201, ≥97% (HPLC)
Sigma-Aldrich
Leptin from rat, ≥97% (SDS-PAGE), recombinant, expressed in E. coli, lyophilized powder