The CYP1A1 connection between enterolactone and breast cancer risk

Enterolactone (EL), a mammalian enterolignan, is a gut microbe-generated plant-lignan derivative. Although observational data are controversial, meta-analyses have affirmed that plant lignan-rich diets, or high serum EL reduce breast cancer risk, or the associated mortality, in post-menopausal women. However, the mechanistic basis is unknown. Here we show that EL antagonizes AHR to reduce CYP1A1 mRNA expression in MCF-7 breast cancer cells. Intriguingly, it increases CYP1A1 protein, a mediator of xenobiotic response, which is frequently expressed in breast tumors, and implicated in cell proliferation and survival. EL’s effect on CYP1A1 expression is similar to estrogen, and mediated via ERα. But, by virtue of partial ERα agonism/antagonism, EL attenuates estrogen-mediated increase in CYP1A1 protein. These data suggest potential mechanisms underlying EL’s beneficial effects in breast cancer. In the face of xenobiotic exposure, its AHR antagonism may reduce the generation of cancer-inducing genotoxic agents. With declining levels of estrogen in post-menopausal women, EL may antagonize estrogen-mediated induction of CYP1A1 protein, and the associated proliferation of mammary epithelial cells.