Chang Chao-Ching, Wu Meng-Ju, Yang Jer-Yen, Camarillo Ignacio G, Chang Chun-Ju
Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana.
Center for Cancer Research, Purdue University, West Lafayette, Indiana.
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.
肥胖与乳腺癌进展相关，但潜在机制仍不清楚。在此我们报告肥胖相关脂肪因子瘦素如何调节转录途径，以沉默促进恶性进展的乳腺癌干细胞样细胞（CSC）中上皮稳态的遗传程序。利用全基因组ChIP-seq和RNA表达谱分析，我们确定了活化的STAT3和G9a组蛋白甲基转移酶在miR-200c表观遗传沉默中的作用，miR-200c促进由瘦素受体（OBR(hi)）细胞表面水平升高所定义的乳腺CSC的形成。抑制STAT3/G9a途径可恢复miR-200c的表达，进而将CSC表型逆转至更分化的上皮表型。在饮食诱导肥胖驱动的大鼠乳腺癌模型中，STAT3阻断抑制了CSC样OBR(hi)群体并消除了肿瘤进展。总之，我们的结果表明靶向STAT3-G9a信号传导如何在肥胖相关乳腺癌进展过程中调节CSC可塑性，提示一种抑制CSC库并限制乳腺恶性肿瘤的新型治疗模式。
