Imbalanced Expression of Inhibin and Activin Subunits in Primary Epithelial Ovarian Cancer

Abstract

Objectives.Inhibins and activins are related gonadal peptides with opposing biologic actions on gonadotropin regulation, cell differentiation, and proliferation. The previous study of activin in ovarian cancer cell lines suggests that activin may promote growth of ovarian cancer. Elevated serum inhibin levels were also found in ovarian cancer patients; however, the source of elevated inhibin is unknown. This study is designed to examine the expression of inhibin and activin subunits as well as activin receptor in primary ovarian epithelial tumors to explore their role in the process of ovarian epithelial tumorigenesis.Methods.The protein and mRNA expression of α and βA subunits of inhibin/activin as well as of activin receptor mRNA were examined with immunohistochemistry (IHC) and reverse transcription–polymerase chain reaction (RT–PCR) in 112 ovarian carcinomas. Cases included 59 serous, 23 endometrioid, 16 mucinous, 9 clear cell, and 5 undifferentiated carcinomas. We also tested normal ovary and benign and borderline ovarian tumors for comparison. These included 17 ovarian surface epithelial samples, 6 serous and 5 mucinous cystadenomas, and 9 serous and 7 mucinous tumors of low malignant potential. A total of 139 ovarian tumors were analyzed by IHC and a total of 63 ovarian tumor samples were tested by RT–PCR.Results.Inhibin α subunit expression was found in 47% of ovarian surface epithelia and focal α immunoreactivity was seen in tumor stroma, but was not found in the epithelial component of ovarian cystadenomas, tumors of low malignant potential (LMP), or carcinomas. Activin βA subunit was expressed in 93% of surface epithelia, in the epithelial component of all cystadenomas, in 81% of LMP tumors, and in 72% of carcinomas, but not in tumor stroma. Activin expression did not correlate with histologic grades, tumor types, and surgical stages. Activin receptor type I and II mRNA-amplified products were found in virtually all the surface epithelial samples and ovarian tumors.Conclusions.The data suggest that imbalanced expression of inhibin and activin subunits in ovarian surface epithelium may represent an early event which leads to epithelial proliferation. Unopposed βA and activin receptor expression in epithelial compartment of ovarian tumors suggest that activin may be available as autocrine and/or paracrine factors in ovarian epithelial tumors. But exact roles of inhibin and activin in ovarian epithelial tumors remain to be defined.