Differential Roles of Estrogens in Obesity-mediated ER+ Breast Cancer Development

ended

Observational studies indicate that obesity and the risk of developing estrogen receptor-positive (ER+) breast cancers has an inverse association in premenopausal women, but a positive association in post-menopausal women. Breast cancer risk rises steeply after menopause, when estradiol decreases markedly and estrone become the major serum estrogen. Adipose tissue express high levels of the enzyme aromatase, being the major site of estrogen synthesis after menopause. Obesity in postmenopausal women correlates with increased serum estrone levels. Obesity and higher estrone, but not estradiol, are correlated with increased risk of ER+ breast cancer in postmenopausal women. Obesity mediates a chronic inflammatory state through NF-kB pathway activation of pro-inflammatory cytokine expression. The chronic inflammatory milieu established in the obese adipose tissue may be associated to the increased risk of developing several cancer types, including postmenopausal ER+ breast cancer. It is known that estradiol inhibits NF-kB activation through different molecular mechanisms. However, the role of estrone in regulating the NF-kB pathway has not been studied yet. Notably, low intra-tumor expression of enzymes converting estrone into estradiol, and overexpression of enzymes that convert estradiol into estrone are both associated with a worse outcome in ER+ breast cancer patients. This proposal pursue to elucidate the role of estrone in the increased risk of developing ER+ breast cancer in obese postmenopausal women. We hope to determine the roles of estrone and estradiol in regulating NF-kB pathway in adipocytes and ER+ normal epithelial mammary cells. We will also determine if enzymes involved in estradiol to estrone conversion have an oncogenic role in the development of this disease. Data obtained from this work have the potential to identify new markers and therapeutic targets against ER+ breast cancers, and lead to the design of new strategies for its prevention.