A NOVEL ENDOCRINE DISRUPTING AGENT AND BREAST CANCER

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DESCRIPTION (provided by applicant): Endocrine disruptive (ED) agents in ground corncob bedding and foods block male and female sexual behavior and cyclicity in the rat and stimulate breast and prostate cancer cell proliferation. These agents separate into two components (Peak I-CM and Peak II-CM) during HPLC. The mitogenic agents in Peak I-CM (THF-diols) were identified as an isomeric mixture of 9, (12)-oxy-10, 13-dihydroxystearic acid and 10, (13)-oxy-9, 12-dihydroxystearic acids which block male and female sexual behavior and cyclicity. The mitogenic agents in Peak II-CM (LTX-diols) were identified as an isomeric mixture of leukotoxin-diol (LTX-diol) and isoleukotoxin-diol (iLTX-diol) that will be assessed as EDs in the proposed studies. The objectives of the proposed research are to identify the most biologically active synthetic THF-diol and LTX-diol isomers, define the nature of their interaction in modulating endocrine function and breast cancer cell proliferation and define specific biochemical sites regulated by these compounds in these systems. The most active THF-diol and LTX-diol isomer will be isolated and identified separately (Specific Aim 1) and whether they act additively or synergistically to stimulate breast cancer cell proliferation (cell cycle transition and apoptosis) and modify male and female sexual behavior and cyclicity will be determined (Specific Aim 2). The concentrations of THF-diol and/or LTX-diol isomers in tissues and blood from rats given "ED" doses of the compounds will be quantified by GC/MS and whether LTX-diols are precursors to THF-diols in rats will be studied (Specific Aim 3). The abilities of THF-diol and LTX-diol isomers to promote dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in rats (Specific Aim 4), and to stimulate the proliferation (cell cycle transition and apoptosis) of estrogen receptor (ER) positive (MCF-7) or ER-negative (MDA-MB-231 cells) breast cancer cells in vitro or in vivo (in nude mice) by modulating phospholipase A2 (PoA), cyclooxygenase (COX), lipoxygenase (LOX) and aromatase will be evaluated (Specific Aim 5). Leukotoxins are known to affect NO release and it is possible that LTX-diol and THFdiol isomers inhibit female sexual behavior (Lordosis) by disrupting nitric oxide (NO) dependent pathways controlling LHRH release. This will be evaluated (Specific Aim 6). If THF-diols and LTX-diols impact endocrine and cell regulatory pathways by controlling LHRH release and lipogenic products that control cell proliferation, they likely have a major impact on behavioral and reproductive response profiles and cancer growth rates in experimental animals. Over the last decade, linoleic acid has replaced stearic acid in our diet. As metabolites of linoleic acid, increased intake of THF-diols and LTX-diols may influence human health and development. The proposed studies represent a critical step in defining target pathways for ultimately determining the mechanism of action of these compounds.