Estrogen and Human Breast Cancer

Abstract

Breast cancer is the most common neoplastic disease in women worldwide. Development of breast cancer is profoundly influenced by prolonged exposure to estrogens, but the role of estrogen in the development of human breast cancer has remained elusive. There is evidence that in situ metabolism of estrogens by estrone sulfatase and aromatase results in a high level of active estrogens in the breast. Two mechanisms have been considered to be responsible for the potential carcinogenicity of estrogens: receptor-mediated hormonal activity and cytochrome P450-mediated metabolic activation. The receptor-mediated hormonal activity of estrogen has generally been related to stimulation of cellular proliferation, resulting in more opportunities for accumulation of genetic damages leading to carcinogenesis. Since local synthesis of estrogen in the stromal component can increase the estrogen levels and growth rate of breast carcinoma, a paracrine mechanism is likely to account for interactions between aromatase-containing stromal cells and estrogen receptor-containing breast tumor epithelial cells. In addition, expression of the estrogen receptors occurs in cells other than the proliferating cells, suggesting that another paracrine mechanism is operative to mediate the biological response to estrogens. More importantly, estrogen may not need to activate its nuclear receptors to initiate or promote breast carcinogenesis. There is evidence that oxidative catabolism of estrogens mediated by various cytochrome P450 complexes constitutes a pathway of their metabolic activation and generates reactive free radicals and intermediate metabolites that can cause oxidative stress and genomic damage directly. Estrogen-induced genotoxic effects include increased mutation rates and compromised DNA repair system that allows accumulation of genomic lesions essential to estrogen-induced tumorigenesis. However, metabolism of estrogen in normal human breast epithelial cells is largely unclear. More importantly, the carcinogenic potential of estrogens in normal human breast epithelial cells awaits to be elucidated.