Prolonged exposure to estrogens increases the risk of breast cancer in women. Estrogens increase proliferation (estrogen hormonal carcinogenesis) and are metabolized to carcinogenic 4-hydroxy metabolites (estrogen chemical carcinogenesis), which leads to genetic mutations and malignant transformation. The levels of estrogen metabolites can be altered by modulating several key steps in the estrogen chemical carcinogenesis pathway, including expression of P450 1B1 and several detoxification enzymes. Furthermore, inflammatory mediators increase carcinogenic metabolites by fuelling the expression of P450 1B1. Thus, an ideal therapeutic agent would decrease inflammatory mediators and P450 1B1 expression, yet upregulate detoxification enzymes. We previously determined that hops increased Phase II detoxification enzymes (NQO1 and GST), and recently determined that hops is anti-inflammatory in MCF-10A ER(-) normal breast epithelial cells and MCF-7 ER(+) breast cancer cells by reducing iNOS expression and NF-?B-luciferase reporter activity, respectively. We then analyzed the effect of hops on cytokine (TNF-a and IFN-?) induced P450 1B1 expression and estrogen metabolism in MCF-10A breast cells. We determined that hops and its active constituent 8-PN additively increased P450 1B1 expression, yet other constituents of hops, xanthohumol and isoxanthohumol, had no effect. We also determined that hops with cytokines increased 4-hydroxy estrogen metabolites. On the other hand, we found that a licorice extract inhibited cytokine-induced expression of P450 1B1. Hence, our data strongly suggests that botanicals used for women's health in combination with cytokines significantly modulate inflammatory-driven P450 1B1 expression and estrogen metabolism. We will continue to study the effect of these botanicals and their constituents on inflammatory-driven malignant transformation of MCF-10A cells, to determine their overall effect on inflammatory-driven estrogen carcinogenesis and provide predictions regarding their safety and efficacy in women.

Botanicals used for women's health modulate inflammatory-driven estrogen carcinogenesis in MCF-10A cells

248th National Meeting (2014)

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