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

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 promot...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2015-06, Vol.75 (11), p.2375-2386
Main Authors: Chang, Chao-Ching, Wu, Meng-Ju, Yang, Jer-Yen, Camarillo, Ignacio G, Chang, Chun-Ju
Format: Article
Language:English
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Summary: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.
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-14-3076