Inhibition of STAT3 signaling blocks obesity-induced mammary hyperplasia in a mouse model

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 beta (denoted as PV) with haplodeficiency of the Pten gene (Thrb(PV/PV)Pten(+/-)mice). We previously showed that adult nulliparous female ThrbPV/PVPten+/-mice developed extensive mammary hyperplasia and breast tumors. In this study, we induced obesity in ThrbPV/PVPten+/-mice by feeding them a high fat diet (HFD). We found HFD exacerbated the extent of mammary hyperplasia in ThrbPV/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.