Analysis of protein kinase C delta (PKC δ ) expression in endometrial tumors

Summary Endometrial cancer is the most common gynecologic malignancy in the United States. However, its underlying molecular mechanisms are poorly understood; and few prognostic indicators have been identified. The protein kinase C (PKC) family has been shown to regulate pathways critical to malignant transformation; and in endometrial tumors, changes in PKC expression and activity have been linked to a more aggressive phenotype and poor prognosis. We have recently shown that PKC δ is a critical regulator of apoptosis and cell survival in endometrial cancer cells; however, PKC δ levels in endometrial tumors had not been determined. We used immunohistochemistry to examine PKC δ protein levels in normal endometrium and endometrioid carcinomas of increasing grade. Normal endometrium exhibited abundant nuclear and cytoplasmic staining of PKC δ confined to glandular epithelium. In endometrial tumors, decreased PKC δ expression, both in intensity and fraction of epithelial cells stained, was observed with increasing tumor grade, with PKC δ being preferentially lost from the nucleus. Consistent with these observations, endometrial cancer cell lines derived from poorly differentiated tumors exhibited reduced PKC δ levels relative to well-differentiated lines. Treatment of endometrial cancer cells with etoposide resulted in a translocation of PKC δ from cytoplasm to nucleus concomitant with induction of apoptosis. Decreased PKC δ expression, particularly in the nucleus, may compromise the ability of cells to undergo apoptosis, perhaps conferring resistance to chemotherapy. Our results indicate that loss of PKC δ is an indicator of endometrial malignancy and increasing grade of cancer. Thus, PKC δ may function as a tumor suppressor in endometrial cancer.