title: Leptin-STAT3-G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression.
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.
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana.|Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Chao-Ching
authors.initials: CC
authors.lastname: Chang
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana.|Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Meng-Ju
authors.initials: MJ
authors.lastname: Wu
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana.|Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
authors.affiliation: Center for Cancer Research, Purdue University, West Lafayette, Indiana.|Department of Biological Sciences, Purdue University, West Lafayette, Indiana.
authors.forename: Ignacio G
authors.initials: IG
authors.lastname: Camarillo
authors.affiliation: Department of Basic Medical Sciences, Purdue University, West Lafayette, Indiana.|Center for Cancer Research, Purdue University, West Lafayette, Indiana.
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006649:Histocompatibility Antigens / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000235:genetics*; D061986:MCF-7 Cells; D015674:Mammary Neoplasms, Animal / Q000235:genetics / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D051381:Rats; D054411:Receptors, Leptin / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000235:genetics*
chemical_list: D006649:Histocompatibility Antigens; D020738:Leptin; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase
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