This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kelley, K. M. M. Articles by Ratnam, M. Search for Related Content PubMed PubMed Citation Articles by Kelley, K. M. M. Articles by Ratnam, M.

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.

This article has been cited by other articles:

				S. Safe and K. Kim Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways J. Mol. Endocrinol., November 1, 2008; 41(5): 263 - 275. [Abstract] [Full Text] [PDF]

				J. Lin, I-M. Lee, N. R Cook, J. Selhub, J. E Manson, J. E Buring, and S. M Zhang Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women Am. J. Clinical Nutrition, March 1, 2008; 87(3): 734 - 743. [Abstract] [Full Text] [PDF]

				A. Shatnawi, T. Tran, and M. Ratnam R5020 and RU486 Act as Progesterone Receptor Agonists to Enhance Sp1/Sp4-Dependent Gene Transcription by an Indirect Mechanism Mol. Endocrinol., March 1, 2007; 21(3): 635 - 650. [Abstract] [Full Text] [PDF]

				T. Tran, A. Shatnawi, X. Zheng, K. M.M. Kelley, and M. Ratnam Enhancement of Folate Receptor {alpha} Expression in Tumor Cells Through the Glucocorticoid Receptor: A Promising Means to Improved Tumor Detection and Targeting Cancer Res., May 15, 2005; 65(10): 4431 - 4441. [Abstract] [Full Text] [PDF]