Loss of GATA4 and GATA6 expression specifies ovarian cancer histological subtypes and precedes neoplastic transformation of ovarian surface epithelia.

Abstract

The family of zinc finger-containing GATA transcription factors plays critical roles in cell lineage specification during early embryonic development and organ formation. GATA4 and GATA6 were found to be frequently lost in ovarian cancer, and the loss is proposed to account for dedifferentiation of the cancer cells.We further investigated the expression of GATA4 and GATA6 in ovarian surface epithelial lesions and histological subtypes of ovarian carcinomas by immunostaining. GATA4 and GATA6 were found to be absent in high percentages (80 to 90%) of serous, clear cell, and endometrioid ovarian cancer examined. In contrast, both were found positive in 11 out of 12 cases of mucinous carcinomas, suggesting the expression of the GATA factors can distinguish mucinous cancer from other histological subtypes. GATA4 was frequently lost in preneoplastic lesions such as morphologically normal inclusion cysts and epithelial hyperplasia adjacent to malignant cells. The loss of GATA6 correlates closely with neoplastic morphological transformation of ovarian surface epithelia. In culture, GATA4 expression was progressively reduced upon passaging primary ovarian surface epithelial cells, which correlated with changes in histone modification of the GATA4 locus. A reduced GATA6 gene dosage as in GATA6 (+/-) mice led to an increased pre-neoplastic changes and inclusion cysts in the ovaries, suggesting the loss of GATA6 contributes to ovarian cancer development.This study suggests that the expression status of GATA4 and GATA6 may dictate distinct pathologic pathways leading to serous or mucinous ovarian carcinomas. The readily loss of GATA4 expression through changes in chromatin conformation suggests a potential non-phenotypic initiating event, leading to subsequent loss of GATA6, morphological transformation, and ultimate tumorigenesis.