Leptin–STAT3–G9a signaling promotes obesity-mediated breast cancer progression
Cancer research, 2015•AACR
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 …
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 …
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 (OBRhi). 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 OBRhi 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. Cancer Res; 75(11); 2375–86. ©2015 AACR.
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