Van Breemen: Project 2; Botanicals Affect Resilience Through Modulation of Estrogen Carcinogenic Pathways (Bolton)

$366,473P50FY2015ATNIH

University Of Illinois At Chicago, Chicago IL

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Abstract

The longer women are exposed to estrogens the higher the risk of developing hormone-dependent cancers. The mechanisms of estrogen carcinogenesis are not understood. o-Quinones are known metabolites of estrogens and they cause DNA damage. We hypothesize that women's health botanicals (Overview; Table 4) stimulate resilience by inhibiting inflammation-driven estrogen carcinogenesis. Specific Aims: Aim 1. What is the effect of botanicals/compounds on estrogen metabolism? Metabolism of estrogens will be studied in MCF- 10A cells. The ability of botanicals/compounds to induce/inhibit key metabolic pathways will be assessed by quantifying estrogen metabolites (LC-MS/MS, Core D) and analyzing enzymatic activity, gene, and protein expression levels. Aim 2. What is the effect of botanicals/compounds on inflammation-driven estrogen metabolism? There is a direct link between inflammation and estrogen carcinogenesis and women's health botanicals have documented anti-inflammatory activities. Experiments in MCF-10A cells will measure the effect of botanical/compounds on NF-?B, iNOS, PGE2 and COX-2. We will study the effect of botanicals/compounds on cytokine induced enzymes and inflammatory-driven estrogen metabolism (cytokine treated MCF-10A cells, co-culture MCF-10A/macrophages). Aim 3. What is the effect of botanicals/compounds on estrogen carcinogenesis? We have shown that hops and xanthohumol (XH) inhibit estradiol-induced transformation of MCF-10A cells to a malignant phenotype and other potentially active botanicals/compounds will be studied in this breast cancer model. The effect of the other botanicals/compounds on reduction of estrogen induced ROS formation and DNA damage will be analyzed in these cells. The transformation assay will also be performed in the presence of cytokines and/or in the MCF-10A cell/macrophage co-culture system. The estrogen carcinogenesis ACI rat model will be used to examine botanical modulation of estradiol metabolism, inflammatory biomarkers, and tumor formation in vivo. The goal of this aim is to determine if botanicals stimulate resilience by inhibiting estrogen carcinogenesis in vivo, which could protect women from hormone dependent cancers.

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