Endocrine Abstracts

Obesity is associated with an increased risk of hormone receptor positive breast cancer after menopause. The aromatase enzyme catalyzes the conversion of androgens into oestrogens and the breast adipose-specific expression of aromatase is hypothesized to be a major driver of breast cancer growth when ovarian oestrogen biosynthesis has ceased. We have found that aromatase is elevated in breast adipose stromal cells in relation to obesity and menopausal status. Furthermore, obesity-associated local and systemic factors were found to be important drivers of aromatase expression in the breast fat, in part via effects on metabolic pathways, including LKB1/AMPK, p53, HIF1α and PKM2. Importantly, these same factors and metabolic pathways have been shown to regulate energy homeostasis and the growth of breast cancer cells directly. Recently, we have discovered that the gut-derived peptide hormone ghrelin and its unacylated form, decreased in obesity, are potent negative regulators of aromatase expression in the breast fat and that they suppress the production of inflammatory mediators from adipose tissue macrophages, believed to be key drivers of aromatase and breast cancer growth in obesity. Moreover, unacylated ghrelin directly inhibits the growth of hormone receptor positive breast cancer cells that are sensitive and resistant to endocrine therapy. These findings support the hypothesis that we can harness our understanding of the mechanistic link between obesity and breast cancer to develop novel therapies for breast cancer.