Breast cancer and flavonoids - a role in prevention

Endogenous estrogens, such as 17β-estradiol (E2), are implicated in the development of breast cancer. The putative mechanisms by which estrogens exert the carcinogenic effects have been recognized to involve the redox cycling of estrogen metabolites and subsequent estrogen-DNA adduct formation as well as the estrogen receptor-dependent pathway of estrogen-induced cell growth. The former pathway is regulated by phase I enzymes, mainly cytochrome P450 (CYP) 1A1, 1A2, and 1B1. Among them, CYP1B1 predominantly catalyzes the C4-position of E2 and forms carcinogenic 4-hydroxy-E2 (4-OHE2), whereas CYP1A1 and CYP1A2 convert E2 to noncarcinogenic 2-hydroxy-E2. Formed 4-OHE2 is further oxidized to semiquinones and quinones, which form DNA adducts, leading to mutagenic lesions. Consequently, CYP1B1 is highly expressed, and 4-OHE2 is predominantly detected in estrogen target neoplastic tissues. Moreover, invasion and metastasis are also involved in the development of breast cancer. Epidemiological studies suggest an inverse association between a higher intake of flavonoids and breast cancer risk. Flavonoids, which are widely distributed in the plant kingdom, have been recently reported as candidate compounds that can exert chemopreventive effects in estrogen-dependent or independent breast cancer. In this review, we provide a comprehensive overview of breast cancer and chemoprevention by flavonoids, mainly focusing on ER-mediated hormonal regulation, redox cycling of estrogen metabolites, and selective inhibition of CYP1B1.