Diet, Estrogen, and Breast Cancer

We hypothesize that, compared to AE mice on an unrestricted high fat diet (ad lib HFD), AE mice on a time-restricted high fat diet (tRF-HFD) will show (1) normalized weight, (2) lower aromatase activity in breast adipose tissue, (3) reduced local estrogen in the breast, and (4) a lower predisposition to developing breast cancer via the AMPK pathway. Mechanistically, we propose that tRF-HFD-induced weight loss triggers AMPK signaling pathways that downregulate aromatase expression via the proximal promoter II/I.3 in breast adipose tissue, thereby decreasing estrogen production and preventing breast cancer development. Our long-term goal is to determine the mechanism responsible for the link between obesity and increased risk of developing postmenopausal breast cancer. Specifically, we propose that tRF-HFD-induced weight loss triggers AMPK signaling pathways that decrease aromatase expression via a robust downregulation of its proximal promoter II/I.3 region in breast adipose tissue. The two objectives of this proposal are: (1) to assess the effect of tRF-HFD or ad lib HFD on aromatase expression via promoter PII/I.3 and estrogen production; and (2) to determine the effect of tRF-HFD or ad lib HFD on mammary carcinogenesis. As a future aim, we plan to define the molecular mechanisms underlying tRF-HFD regulation of the AMPK/aromatase pathway and estrogen formation in mammary tissue. Aim 1: To assess the effect of tRF-HFD or ad lib HFD on aromatase expression via promoter PII/I.3 and estrogen production. Aim 2: To determine the effect of tRF-HFD or ad lib HFD on breast carcinogenesis.