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Modulation of the Folate Receptor Gene by the Estrogen Receptor

Mechanism and Implications in Tumor Targeting^{1 ,2}

Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo, Ohio 43614-5804

The folate receptor (FR) type is a promising target for diagnostic imaging agents and therapeutic intervention in major subtypes of gynecological malignancies; however, the receptor levels in the tumors are variable and are generally relatively low in estrogen receptor (ER)-positive tumors. Here we report that the FR- gene promoter is repressed in the presence of 17ß-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182,780 in a promoter-specific and ER--dependent manner in carcinoma cell lines including HeLa (cervical carcinoma), BG-1 (ovarian carcinoma), and IGROV-1 (ovarian carcinoma). The ligand and ER dose response of the FR- promoter and its time course paralleled those of a classical estrogen response element-mediated effect. Antiestrogens produced an ER-dependent increase of up to 36-fold in the expression of the endogenous FR- gene. Deletion analysis and FR-/SV40 promoter chimeras showed that the ER effect is mediated exclusively within the G/C-rich region in the TATA-less P4 promoter of FR-; electrophoretic mobility shift analysis demonstrated interaction of ER at only one of three G/C-rich elements. ER-ß only modestly affected FR- promoter activity but did not diminish the ER--mediated effects. The ER corepressor, SMRT, enhanced the repression by 17ß-estradiol/ER, but ER coactivators, including SRC family members, did not appreciably impact the ER ligand response. The results suggest that in ER+ tumors, FR- expression is directly and actively suppressed and predict that a brief treatment with antiestrogens will boost FR- expression by passive derepression, enhancing the efficacy of FR-targeted diagnostic and therapeutic applications. They also reveal novel aspects of gene repression by ER.

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