HUMAN MAMMARY STROMA AS A TARGET FOR ORGANOCHLORINES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. ABSTRACT Although the overall breast cancer (BC) incidence rate for African American (AA) women is lower than for White women, among AA women under the age of 45 the rates are higher. The inherited forms of BC account only for 5-10% of all cases, leaving 90-95% of all cases to be contributed by environmental factors, including chemical exposure. Work in this laboratory is focused on determining how exposures to environmental chemicals such as organochlorines are conferring not only increased risk of breast cancer among young African American women but also the presentation of a more aggressive form of the disease with a higher mortality rates than in white women. This proposal will test the hypothesis that the disparite exposure of AA women to higher levels of organochlorines than White women and the persistence of these chemicals in their breast adipose tissues will modify the stromal function resulting in disruption of stromal-epithelial interaction, which leads to deregulation of epithelial growth and differentiation. The following three specific aims will be addressed using an in vitro cell culture system of human mammary epithelia and stromal fibroblasts from African American and white women donors. Aim 1. To characterize the heterogeneity of breast epithelia and fibroblasts with respect to their estrogen-responsiveness and how is it modified by exposure to organochlorines. Aim 2. To verify that activation of estrogen receptors by organochlorines affects expression of stromal growth factors, which determine their growth and epithelial growth. Aim 3. To identify the stromal factors expressed in response to estrogens and their modification by organochlorines exposure, by evaluating global gene expression of cytokines, growth factors, extracellular matrix components, proteases and angiogenic factors using specialized oligonucleotide microarray chips; and by protein expression profiling of both synthesized and secreted proteins using comparative proteomics. Such studies will provide mechanistic approach for how these hormonally active chemicals target the mammary stromal epithelial interaction to induce breast carcinogenesis.