Protein kinase C alpha expression is inversely related to ER status in endometrial carcinoma: Possible role in AP-1-mediated proliferation of ER-negative endometrial cancer

Objective. Tamoxifen is the most widely used antiestrogen to treat all stages of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen acts as a partial estrogen in the uterus and is known to increase the risk of endometrial cancer by two- to threefold. Recent evidence indicates that there is a connection between tamoxifen resistance and activation of the activator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKCα), an upstream activator of the AP-1 pathway, in hormone-independent breast cancer and antiestrogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormone-independent breast cancer and determine whether specific PKC isozyme alterations correlated with known clinicopathological features of endometrial cancer. Methods. The PKC isozyme profile of endometrial carcinomas from 42 patients who were not previously exposed to antiestrogens was examined by Western blot. The relationship between PKC isozyme expression and key prognostic factors for endometrial carcinoma including hormone receptor status, tumor grade, stage, size, and depth of myometrial invasion was examined using the Spearman's rho correlation coefficient. Results. As previously found in breast cancers, PKCα and estrogen receptor alpha (ERα) expression are inversely related (r_s = -0.35, P = 0.046). We report significant inverse correlations among ER/progesterone receptor (PR) expression and tumor grade (r_s = -0.49, P = 0.001 and r_s = -0.44, P = 0.004, respectively), ER, and depth of myometrial invasion (r_s = -0.40, P = 0.009). There were no other significant correlations between PKC isozyme expression and other key prognostic factors examined. Conclusion. This study indicates that, similar to what was previously observed in breast cancer, PKCα and ER expression is inversely related in endometrial cancer. PKCα expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCα overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.