Leptin-STAT3-G9a signaling promotes obesity-mediated breast cancer progression
Menée in vitro et in vivo, cette étude met en évidence des mécanismes par lesquels, dans le contexte d'une tumeur mammaire liée à une obésité, la voie de signalisation leptine-STAT3-G9a favorise la prolifération de cellules souches cancéreuses
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 which 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 cancer stem-like cells (CSC) 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.