INCREASED IMMUNOSTAINING OF FIBULIN-1, AN ESTROGEN-REGULATED PROTEIN IN THE STROMA OF HUMAN OVARIAN EPITHELIAL TUMORS

Fibulin-1, an extracellular matrix protein, is secreted by human ovari an metastatic cancer cell lines under estrogen stimulation. Fibulin-1 expression was quantified by immunohistochemistry and computer-aided i mage analysis in 44 human ovarian epithelial tumors and 14 normal ovar ies. The fibulin-1 staining intensity in proximal stroma, close to the surface of epithelial cells and tumor cells, progressively increased from normal ovaries to serous carcinomas. In all lesions, excluding cy stadenomas, fibulin-1 accumulation was higher in proximal stroma than in distant stroma. In situ hybridization demonstrated strong fibulin-1 gene expression in epithelial cells of serous ovarian carcinomas and some cysts. The weak expression of fibulin-1 RNA in some stromal cells of these tumors could not explain the strong fibulin-1 protein accumu lation in tumor stroma, which was therefore mostly produced by tumor e pithelial cells. In carcinomas, fibulin-1 staining was not correlated with the percentage of estrogen receptor-alpha (ER alpha)-stained nucl ei but was inversely correlated with the progesterone receptor. Howeve r, in cystadenomas and borderline tumors, both fibulin-1 and ER alpha protein levels increased, in comparison with normal ovaries, suggestin g an effect of estrogens in the early steps of tumorigenesis. This fib ulin-1 overexpression, demonstrated in vivo in ovarian carcinomas, mig ht be a useful indicator for predicting cancer risk and/or aggressiven ess.