Differential regulation of folate receptor isoforms in normal and malignant tissues in vivo and in established cell lines. Physiologic and clinical implications

Abstract

Background. Despite significant differences in ligand binding between the two known isoforms of the human membrane folate receptor (FR), designated herein as FR β (placenta) and FR‐α (placenta, KB cells), little is known about their tissue specificities, and there is no report on the relative expression of FR‐β in any tissue other than in placenta. Methods. The mRNA for each FR isoform in a wide variety of normal fetal and adult tissue explants, primary normal cell cultures, malignant tumor explants, and established tumor cell lines was estimated by a polymerase chain reaction assay. Total receptor levels were estimated by a [3H] folic acid binding assay. Results. Both the FR isoforms were expressed in fetal as well as adult tissues. Normal tissues generally expressed low to moderate amounts of FR‐β. FR‐α alone was expressed in normal epithelial cells and was frequently strikingly elevated in a variety of carcinomas, with the exception of squamous cell carcinomas of the head and neck. In contrast, a variety of malignant tissues of nonepithelial origin generally expressed elevated levels of FR‐β alone. Established tumor cell lines expressed FR‐α virtually alone and did not reflect FR expression patterns in vivo. KB cells and JEG‐3 cells grown at low folate concentrations further up‐regulated FR‐α but not FR‐β. Conclusions. Although FR‐β is the more common isoform, FR‐α and FR‐β are differentially regulated in normal tissues, carcinomas, nonepithelial malignancies, and immortalized cells or in response to changes in extracellular folate concentrations. The tissue specificity of FR isoforms and their elevation in malignant tissues may be a significant factor in FR‐mediated folate uptake, in tissue responsiveness to promising novel antifolates, and in FR‐related immunodiagnosis/immunotherapy.

Folate receptor overexpression is associated with poor outcome in breast cancer

“…This is consistent with previous reports showing that most breast cancers studied had upregulated the folate receptor to some extent, when compared with normal breast epithelial cells. 10 In our series of breast cancers reported here, we saw no correlation between strong FR expression and ER positivity or negativity. This lack of correlation between FR and ER expression was somewhat surprising in view of observations of Ratnam and coworkers that FR expression is repressed in cultured cancer cells in the presence of 17 b-estradiol and derepressed by the antiestrogens tamoxifen and ICI 182780 in promoter-specific and ER-a-dependent manner.…”

“…6 Distribution and binding studies of the high affinity folate receptor have shown high expression in the majority of ovarian cancers, and lesser degrees of positivity in kidney, breast, uterine and lung cancers. [6][7][8][9][10] Studies in ovarian cancer have shown an association between folate receptor overexpression and tumor aggressiveness. 7,[11][12][13] Studies of folate receptor expression in breast cancers have found varying results, depending on the techniques used and tissues analyzed.…”

“…Ross et al measured mRNA for the folate receptor and found levels to be elevated in five cancers when compared with normal breast specimens; however, the degree of elevation was 10-fold less than that seen in ovarian cancer. 10 Garin-Chesa et al used a mouse monoclonal antibody LK26 to assess folate receptor expression in a variety of fresh-frozen cancers. Of 53 breast cancers studied, two showed homogeneous LK26 expression and another nine, patchy staining.…”

DNA vaccination against the ovarian carcinoma-associated antigen folate receptor α (FRα) induces cytotoxic T lymphocyte and antibody responses in mice

“…17 The ␣ isoform of the folate receptor (FR), a 38-to 40-kDa glycosylphosphatidylinositol-anchored molecule, 18 -20 is expressed at very low levels on the cell surface of normal epithelial tissues; at medium levels on the kidney, lung, and breast; and at high levels on placental tissue. [21][22][23] Overexpression of FR␣ has been detected on ϳ90% of ovarian carcinomas 23,24 in association with the progression of the disease, 25 on epithelial tumors derived from the uterus, and on nervous system tumors. 22 Based on its expression pattern, FR␣ has been used as a target molecule for monoclonal Ab (mAb)-based immunotherapy strategies.…”

Loss of heterozygosity at the 5,10-methylenetetrahydrofolate reductase locus in human ovarian carcinomas

“…a-FBP, which is recognized by the monoclonal antibody MOv18, is moderately expressed in some normal epithelial cells but is present at higher levels in very specialized organs, such as normal fallopian tubes, adult renal proximal and distal tubules and lactating glands. Moreover, a-FBP is overexpressed in a variety of neoplastic tissues, particularly in non-mucinous ovarian carcinomas (80%) and adenomas (approximately 100%), whereas normal ovary, uterus and vagina are negative (Miotti et al, 1987; Received Veggian et al, 1989;Campbell et al, 1991;Coney et al, 1991;Ross et al, 1994). Such a phenotypic characteristic, although not limited to ovarian carcinomas, may suggest that these neoplastic cells have an increased metabolic requirement for folates, the uptake of which can be highly intensified by an increased expression of the high-affinity FBP receptor molecules.…”