Enterolactone, a mammalian enterolignan, differentially modulates CYP1A1 mRNA and protein in MCF-7 breast cancer cells

Enterolactone, 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 enterolactone, reduce breast cancer risk, or the associated mortality in post-menopausal women. However, the mechanistic basis remains poorly understood. Here we show that enterolactone antagonizes aryl hydrocarbon receptor to reduce cytochrome P450 family 1 subfamily A member 1 (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. Enterolactone's effect on CYP1A1 expression is similar to estrogen, and mediated via estrogen receptor α. But, by virtue of partial estrogen receptor α agonism/antagonism, enterolactone attenuates estrogen-mediated increase in CYP1A1 protein. These data suggest potential mechanisms underlying enterolactone's beneficial effects in breast cancer. In the face of xenobiotic exposure, its aryl hydrocarbon receptor antagonism, on one hand, may reduce the generation of cancer-inducing genotoxic agents. While, on the other hand, with the declining levels of estrogen in post-menopausal women, enterolactone may antagonize estrogen-mediated induction of CYP1A1 protein, and the associated proliferation of mammary epithelial cells.