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PDZK1 and GREB1 Are Estrogen-regulated Genes Expressed in Hormone-responsive Breast Cancer^{1, 2}

Department of Surgery, Stanford University, Stanford, California 94305

The function of estrogen in breast cancer proliferation and progression is likely to be due to the expression of a repertoire of genes regulated by estrogen receptor (ER). Using suppression subtractive hybridization, we have isolated a set of 14 estrogen-responsive genes that was differentially expressed in MCF7 cells stimulated by ß-estradiol as compared with unstimulated cells. Tamoxifen repressed the expression of all 14 estrogen-responsive genes. Thirteen of the genes were induced within 6 h of estrogen treatment, indicating that these were early response genes in the ER-regulated pathway. PDZK1 and a new gene, GREB1, demonstrated a significant correlation with ER phenotype in a panel of breast cancer cell lines. Treatment with cycloheximide indicated that ER directly controls GREB1 expression. Three cDNAs (GREB1a, GREB1b, and GREB1c) were isolated by screening a MCF7 cDNA library. These three cDNAs of GREB1 shared extensive sequences through the open reading frame but had divergent 5' untranslated regions, indicating the possibility of multiple promoters regulated by ß-estradiol. Studies in primary breast cancers showed that PDZK1 and GREB1 were overexpressed in ER-positive breast cancers as compared with ER-negative breast cancers by 19-fold and 3.5-fold, respectively. GREB1 was also induced by ß-estradiol in the ER-positive endometrial cell line ECC-1. The pattern of expression suggests a critical role for these two genes in the response of tissues and tumors to ß-estradiol.

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