Expression of folate receptor type alpha in relation to cell type, malignancy, and differentiation in ovary, uterus, and cervix.

The folate receptor (FR) type alpha is known to be frequently overexpressed in ovarian cancer and is the target for a number of novel experimental cancer therapies. The relative levels of FR expression among specific cell types and its relationship to malignant transformation have not been adequately established because of several inherent limitations of the immunocytochemical approaches used previously. We used a quantitative in situ hybridization method to examine the expression of the mRNAs for the known isoforms of FR in paraffin-embedded tissue sections of multiple samples of the various subtypes of ovarian, uterine, and cervical cancers. Benign lesions, as well as the various normal cell types in the ovary, the uterus, and the cervix, were examined similarly. FR mRNA levels were quantitated relative to the transcript levels for beta-actin using NIH Image 1.57 computer software. The results show that the ovary, the uterus, and the cervix present different patterns of FR regulation in differentiation and in malignancy. In the ovary, benign differentiation of the germinal epithelium into mucinous or serous tumors or malignant transformation into mucinous tumors is associated with down-regulation of FR-alpha, whereas FR-alpha expression is retained in malignant lesions of serous and endometrioid differentiation. In contrast, malignant transformation of the glandular epithelial cells of the uterine endometrium is associated with de novo expression of FR-alpha. Heterogeneity in FR expression within malignant ovarian and uterine tumors is related to differentiation. In contrast to the uterus, malignant transformation of glandular epithelial cells in the cervix may frequently result in down-regulation of FR-alpha. These results shed new light for the identification of malignancies suitable for FR-mediated therapies and for prognostic/diagnostic applications of FR. They also provide a phenomenological basis for molecular studies of FR regulation in malignant cells.