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Identification of a Novel Inhibitor of Breast Cell Growth That Is Down-Regulated by Estrogens and Decreased in Breast Tumors¹

Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44122 [B. M. W., M. M. M.], and Department of Pathology, University Hospitals of Cleveland, Cleveland, Ohio 44106 [N. W.]

Lifetime exposure to estrogens is a major risk factor in breast cancer, but the mechanism for this action is not fully defined. To better determine this mechanism, the activation domain of estrogen receptor (ER) was used in yeast two-hybrid screenings. These screenings resulted in the identification of a novel antiproliferative protein, estrogen down-regulated gene 1 (EDG1), of which the mRNA and protein were shown to be down-regulated directly by estrogens. Our studies additionally suggested an important role for EDG1 in ER-mediated breast cancer development. Analysis of 43 invasive breast cancer samples and 40 adjacent normal breast samples demonstrated EDG1 protein levels to be significantly higher in normal breast epithelial tissue as compared with breast epithelial tumor tissue. EDG1 expression levels were also correlated with the proliferation activity and ER status of the tumors to examine the prognostic value of EDG1 in invasive breast tumors. EDG1 expression was more disassociated from proliferative activity as compared with ER expression in tumor cells. A growth regulatory function for EDG1 is additionally indicated by studies wherein overexpression of EDG1 protein in breast cells resulted in decreased cell proliferation and decreased anchorage-independent growth. Conversely, inhibiting EDG1 expression in breast cells resulted in increased breast cell growth. Thus, we have identified a novel growth inhibitor that is down-regulated by estrogens and colocalizes with ER in breast tissue. These studies support a role for EDG1 in breast cancer.

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