PESTICIDE-INDUCED DIFFERENTIATION AND HETEROGENEITY IN BREAST CANCER CELLS

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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. While pesticide-induced carcinogenesis via estrogenic pathways have been suggested, a consensus on whether exposure to estrogenic pesticides is in fact physiologically relevant has yet to be reached. The goal of this study is to examine how estrogenic and non-estrogenic endocrine-active pesticides alone or in combination (i.e., mixtures) may augment or inhibit endocrine responses in breast cancer cells, and whether these interactions might result in a differential selection (directly or indirectly) for an invasive phenotype. The specific hypothesis to be tested is that pesticides alone and in combination can re-model breast cancer cell populations. The objectives of the previous year and current aims are: (1) to examine the estrogen receptor and non-estrogen receptor-mediated effects of pesticides (alone and in combination) on estrogen-sensitive gene transcription in breast cancer cells; and (2) to elucidate whether endogenous cellular pathways may influence the actions of pesticides (alone and in combination) on estrogen-regulated gene expression in breast cancer cells. To date our whole population cell culture studies in both T47-D and MCF-7 breast cancer cell lines have yielded the following new data: HPTE in combination with atrazine in the presence of DHEA-S (steroidal substrates) enhanced estrogen-response element (ERE)-mediated gene expression above HPTE or atrazine treatment alone (i.e., a combinatorial effect: however, only at uM concentrations), and HPTE in combination with IGF-1 and TGF-alpha augments ERE-mediated gene expression above treatment with HPTE alone. On-going research is aimed at determining whether endocrine-active pesticides (alone or in mixtures) may differentially regulate the responsiveness of subpopulations of cells within cancer cell societies. We have begun addressing this aim by overcoming technical considerations related to the imaging of single, individual breast cancer cells (note: the former "Imaging Subcore" has been merged into this research project), and have evaluated the imaging capabilities two systems which are being optimized currently. Current studies are addressing the heterogeneity in responsiveness of breast cancer cells to endocrine active agents (e.g., HPTE) using these novel single cell approaches.