title: Inhibition of STAT3 signaling blocks obesity-induced mammary hyperplasia in a mouse model.
abstract: Compelling epidemiologic evidence indicates that obesity is a risk factor for human cancers, including breast. However, molecular mechanisms by which obesity could contribute to the development of breast cancer remain unclear. To understand the impact of obesity on breast cancer development, we used a mutant mouse that expresses a mutated thyroid hormone receptor β (denoted as PV) with haplodeficiency of thePtengene (ThrbPV/PVPten+/-mice). We previously showed that adult nulliparous femaleThrbPV/PVPten+/-mice developed extensive mammary hyperplasia and breast tumors. In this study, we induced obesity inThrbPV/PVPten+/-mice by feeding them a high fat diet (HFD). We found HFD exacerbated the extent of mammary hyperplasia inThrbPV/PVPten+/-mice. HFD elevated serum leptin levels but had no effect on the levels of serum thyroid stimulating hormone, thyroid hormones, and estrogens. Molecular analysis showed that the obesity-induced hyperplasia was mediated by the leptin/leptin receptor-JAK1-STAT3 pathway to increase key cell cycle regulators to stimulate mammary epithelial cell proliferation. Activated STAT3 signaling led to altered expression in the key regulators of epithelial-mesenchymal-transition (EMT) to augment invasiveness and migration of mammary proliferating epithelial cells. Moreover, treatment of HFD-ThrbPV/PVPten+/-mice with a STAT3 inhibitor, S3I-201, markedly reversed the obesity-induced mammary hyperplasia and reduced EMT signals to lessen cell invasiveness and migration. Our studies not only elucidated how obesity could contribute to mammary hyperplasia at the molecular level, but also, importantly, demonstrated that inhibition of the STAT3 activity could be a novel treatment strategy for obesity-induced breast cancer progression.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892-6264, USA.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Park
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892-6264, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892-6264, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, MD 20892-6264, USA.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
keywords: JAK2-STAT3 signaling; Mammary carcinogenesis; STAT3 inhibitor; obesity; preclinical mouse model; thyroid hormone receptor β mutant