The vast majority of human breast cancers are initially hormone-dependent with estradiol playing a crucial role in their development and evolution (1). However there is relatively little known about how estrogen activation of the estrogen receptor (ER) results in the initiation or promotion of human breast cancer. We have identified a novel gene that is down regulated by estradiol, Estrogen-Down-regulated Gene 1 (EDG1), in breast epithelial cells. Subsequent studies indicate that EDG1 inhibits ERalpha transcriptional activity. A self-contained tetracycline-regulated retroviral vector system (2) has been used to both positively and negatively regulate the expression of EDG1 in breast cancer cells (MCF7 and MDA-MB-231) and normal breast cells (MCF 10A). Compared to control cells, cells that over express EDG 1 (MCF7-EDG 1, MCF 10-EDG1 and MDA-MB-23 1-EDG1) exhibit decreased growth rate, while cells that have decreased EDG1 expression (MCF7-EDG1AS and MCF10-EDG1AS) have enhanced growth rate. Moreover EDG1 overexpression inhibited anchorage independent growth and estrogen-induced MCF7 proliferation. While we see cross talk between estrogen and EDG1, we propose that EDG1 may also function as a tumor suppressor independent of ERa levels. A mechanistic basis for the growth effect of EDG1 is suggested by the interaction of EDG1 with Integrin beta4-interactor protein (p27/BBP) and the 67 kD laminin receptor (67LR). p27/BBP protein interacts with the cytodomain of beta4 integrin and has been proposed to link beta4 integrin with the cytoskeleton, while 67LR binds to laminins and interacts with the alpha6beta4 integrin multimeric complex. Based on our preliminary findings we hypothesize that the growth inhibitory effects of EDG1 in breast cells have ERalpha-dependent and ERalphs-independent components; and EDG1 helps maintain the balance of signaling events generated through the extracellular matrix that regulates normal breast epithelial cell function. To test our hypothesis we will: (1) characterize EdG1 inhibition of ERalpha transcriptional activity and its role in the growth inhibitory effects of EDG1 (2) examine the role of Integrin-beta4-interactor protein and the 67 kD laminin receptor in EDG1 cellular effects and (3) characterize other phenotypic effects of EDG1 and identification of other downstream effectors of EDG1.
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