EXCEED THE SPACE PROVIDED. Breast cancer is a major disease and health care concern that will affect one in every nine women in the U.S. Despite significant discoveries in the past few years concerning genetic risk factors, it is estimated that genetic factors only directly account for approximately 10% of all breast cancer cases. Environmental and dietary factors likelyplay a major role in the etiology of breast cancer, yet we do not yet know what agents increase a women's risk of breast cancer or may be causative agents. Environmental and dietary agents likely interact with genes and gene products to induce breast cancer in women through processes of tumor initiation, promotion, and progression. While there has been much work on mechanisms by which environmental chemicals produce tumor initiation, there has been inadequate work on mechanisms of tumor promotion and progression by these agents. In this competitive renewal of a previously funded 4 yr grant, we have found that a chemical class of known (rodent) mammary carcinogens, polycyclicaromatic hydrocarbons (PAHs, such as benzo[a]pyrene, BaP),mimic growth factor signaling through the epidermal growth factor receptor (EGFR) leading to increased mammary epithelial cell proliferation and survival. Increased cell proliferation and inhibition of cell death are likely important mechanisms of mammaryepithelial cell promotion and progression leading to breast cancer. There appear to be three different pathways by which PAHs, such as BaP alter signaling pathways in mammary epithelial cells, including activation of Ah receptors, increasing Ca2+signaling, and causing oxidative stress. Studies suggest that modulation of intracellular Ca2+ may play an important role in signaling Ca2+-dependent and oxidative stress associated pathways (INK, Erk, and p38 MAP kinases). P450 metabolism is required for BaP to increase intracellular Ca2+ in primary cultures of human mammary epithelial cells (HMEC) and MCF-10A cells, and the aromatic hydrocarbon receptor (AhR) appears to play a critical role in growth regulation and protection of MCF-10A cells from apoptosis. Initial results suggest that redox-cycling BaP-quinones (BPQs) are largely responsible for Ca2+ elevation via an oxidant stress mechanism. We have also discovered that an aldoketoreducatse (AKR1C1) is expressed in MCF-10A cells and that a BaP product of this enzyme, 7,8-BP-quinone (7,8-BPQ) has unique Ca2+-elevating activity in MCF-10A cells. The biochemical mechanism of Ca2+ elevation by 7,8-BPQ may be associated with ryanodine receptor (RyR) activity, as we have recently found that these receptors are highly expressed in MCF- 10A cells. These studies will further define the role of AhR, Ca2+, and oxidative stress signaling pathways in potential mechanisms of breast tumor promotion in MCF-10A cells and normal human mammary epithelial cells (HMEC). The results of these studies should help better define the role of environmental PAHs in the etiology of human breast cancer. I/PERFORMANCE SITE ========================================Section End===========================================
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