Phytoestrogens and Cancer

Southern Univ A&M Col Baton Rouge, Baton Rouge LA

Investigators

Linked publications & trials

Abstract

Dietary phytoestrogens (PEs) have been given considerable attention due to their protective role in[unreadable] certain hormone-dependent cancers. However, the current scientific consensus is that the outcome from[unreadable] increased phytoestrogen intake is unpredictable partly due to a poor understanding of their mechanisms of[unreadable] action in breast cells. Thus, developing a model system for phytoestrogens in breast cancer cells is a critical[unreadable] step in reconciling the possibility of both adverse and beneficial effect of these compounds. The potential[unreadable] mechanisms by which dietary PE may exert cancer protective or anti-estrogenic effects are unknown. Thus,[unreadable] elucidation of these mechanisms is essential in understanding their cancer-protective effects. Currently, no[unreadable] methodology is available to distinguish the specific cancer-protective effects of PE from their well-known[unreadable] estrogenic-like effects. Therefore, to understand the molecular mechanisms of phytoestrogenic chemicals in[unreadable] breast cancer, we have identified novel PE-responsive genes using differential display RT-PCR,[unreadable] representational difference analysis of cDNA, and quantitative RT-PCR. Using these methodologies, we[unreadable] have characterized the expression of one of these genes, PE13.1, that has not previously known to be[unreadable] regulated by PE. This gene is selectively activated by genistein and coumestrol but not by estradiol.[unreadable] Furthermore, its expression is PE specific and estrogen receptor (ER) dependent. Thus, PE13.1 is an ideal[unreadable] candidate to use as a model in understanding the role dietary estrogen plays in cancer prevention at the[unreadable] molecular level. In this proposal, we will test the hypothesis that differences in PE13.1 expression[unreadable] result from activity on the PE-driven upstream enhancer present in the gene and from interaction[unreadable] with a PE/ER complex. Therefore, we will begin to elucidate the mechanisms of regulation of the PE13.1[unreadable] gene at the molecular level by characterizing PE13.1 regulatory elements (aim 1) and, in particular, how PEs[unreadable] in conjunction with the ER lead to PE13.1 transcriptional activation in a cell (aim 2). The key cis-regulatory[unreadable] elements and trans-acting factors will be identified through sequence analysis of the PE13.1 gene,[unreadable] particularly the 5'-flanking region, and through transfection of luciferase reporter constructs into ER-positive[unreadable] (MCF-7 ER+) and ER-negative (MDN-ER-) cells. We will determine which ER subtype is responsible for[unreadable] PE13.1 transcriptional activity and establish if differences in PE13.1 expression parallel differences in ER[unreadable] status in breast tumor cell lines. These experiments will begin to provide a basis of a biochemical model in[unreadable] which to better understand the estrogenic effect of phytoestrogen in breast cancer cells.