Project 176576

Exposure to biohazardous environmental toxicants is linked with an increased risk for breast cancer. While the biomedical literature supporting this relationship is inconclusive, animal studies and tissue culture experiments provide evidence for the biological plausibility. However, the mechanisms are poorly understood and suitable animal models are limited. To elucidate the mechanisms of environmental toxicants on breast cancer development and metastasis my laboratory uses a unique mouse model of breast cancer. Specifically this mouse model expresses the c-erbB2 gene and mimics many of the features of breast cancer including metastasis. Thus unlike conventional animal models, the model we use allows for testing on a background of risk that we think is more relevant to human health. We have shown that exposure to dieldrin, an estrogenic pesticide that is associated with a significant increased risk for breast cancer and decreased survival, dose dependently increased mammary tumour burden together with expression of Brain Derived Neurotrophic Factor (BDNF) and tyrosine kinase receptor B (Trk B), factors important in cancer cell survival and metastasis. Preliminary studies also reveal that dieldrin dose dependently increased cell invasion and survival as well as BDNF and Trk B expression in two human breast cancer cell lines (invasive and non-invasive). Therefore, we postulate that dieldrin exposure will increase breast cancer metastases via binding with the estrogen receptor and stimulation of BNDF expression and Trk B signalling resulting in increased cell invasion and metastasis. This study will provide insight into the mechanisms underlying the increased risk of breast cancer in women exposed to estrogenic chemicals. Since metastasis is associated with poor prognosis and death our results are expected to influence future testing strategies and regulatory approaches to estrogenic chemicals.