Modulation of the folate receptor alpha gene by the estrogen receptor: mechanism and implications in tumor targeting.

Abstract

The folate receptor (FR) type alpha 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-alpha gene promoter is repressed in the presence of 17beta-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182780 in a promoter-specific and ER-alpha-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-alpha 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-alpha gene. Deletion analysis and FR-alpha/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-alpha; electrophoretic mobility shift analysis demonstrated interaction of ER at only one of three G/C-rich elements. ER-beta only modestly affected FR-alpha promoter activity but did not diminish the ER-alpha-mediated effects. The ER corepressor, SMRT, enhanced the repression by 17beta-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-alpha expression is directly and actively suppressed and predict that a brief treatment with antiestrogens will boost FR-alpha expression by passive derepression, enhancing the efficacy of FR-targeted diagnostic and therapeutic applications. They also reveal novel aspects of gene repression by ER.

• Authors: Karen M M Kelley, Brian G Rowan, Manohar Ratnam
• Journal: Cancer research (Cancer Res) Vol. 63 Issue 11 Pg. 2820-8 (Jun 01 2003) ISSN: 0008-5472 [Print] United States
• PMID: 12782587 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Carrier Proteins
• Estrogen Receptor Modulators
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Folate Receptors, GPI-Anchored
• Receptors, Cell Surface
• Receptors, Estrogen
• Tamoxifen
• Fulvestrant
• Estradiol

Topics

• Carrier Proteins (biosynthesis, genetics)
• Estradiol (analogs & derivatives, pharmacology)
• Estrogen Receptor Modulators (pharmacology)
• Estrogen Receptor alpha
• Estrogen Receptor beta
• Female
• Folate Receptors, GPI-Anchored
• Fulvestrant
• Gene Silencing (drug effects, physiology)
• HeLa Cells
• Humans
• Ovarian Neoplasms (genetics, metabolism)
• Promoter Regions, Genetic (drug effects)
• Receptors, Cell Surface
• Receptors, Estrogen (genetics, metabolism, physiology)
• Tamoxifen (pharmacology)
• Transcription, Genetic (drug effects, physiology)
• Transfection
• Tumor Cells, Cultured