MAMMARY CELL SIGNALING PRODUCED BY ENVIRONMENTAL AGENTS

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The incidence of breast cancer has been increasing in the U.S. and other countries for many years. While there is no proven explanation for this increased risk of disease. it appears that environmental and dietary factors may play an important role in breast cancer development. The purpose of this proposal is to examine the influence of environmental chemicals on breast epithelial cell growth and signaling associated with endogenous growth factor receptors. It is hypothesized that environmental and dietary agents may disrupt normal growth factor signaling processes, or at low doses may actually mimic signals generated by endogenous growth factors. Altered responses to endogenous growth factors may play an important role in breast cancer development. We will focus on two important class of environmental agents known as polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) that are present in the air from various emissions and in the diet. PAHs have been shown by the PI to dramatically alter Ca2+-dependent cell signaling in human B and T lymphocytes, and recent studies demonstrate that Ca2+ signaling in human breast epithelial cells is extremely sensitive to activation by PAHs. Since HAHs share may properties with PAHs, we will examine this important class of environmental pollutants (including dioxins, PCBs, and complex mixtures) in this application. We will study PAHs that are well known mammary carcinogens in animals, and HAHs that are suspected tumor promoters. Preliminary studies have shown in human lymphoid cell lines that PAHs exert important effects on Ca2+ homeostasis via activation of enzymes associated with cell signaling (protein tyrosine kinases) as well as those involved in regulation of intracellular Ca2+ homeostasis (Ca2+-ATPase). Many of these same types of enzymes found in lymphocytes also occur in human breast epithelial cells. Therefore, it is likely that breast epithelial cell protein tyrosine kinases (EGFR, IGF-1R, and HER-2/erbB-2) are activated by PAHs. Intracellular Ca2+ measurements will be obtained using fluorescent Ca2+ chelating agents (Fluo-3) via flow cytometry and confocal imaging. We will also examine the influence of PAHs and HAHs on cyclic AMP signaling pathways in human breast cell lines and primary breast epithelial cell cultures. The influence of estrogenic and anti-estrogenic chemicals on PAH and HAH-induced signaling will also be explored. The results of these studies will provide important new information on potential mechanisms of mimicry or modulation of breast epithelial cell growth factor receptors and Ca2+ signaling produced by environmental agents.