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 stag es of estrogen-receptor (ER)-positive breast cancers. However, tamoxifen ac ts 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 th ere is a connection between tamoxifen resistance and activation of the acti vator protein-1 (AP-1) pathway. We have previously reported a possible role for overexpression of protein kinase C alpha (PKC alpha), an upstream acti vator of the AP-1 pathway, in hormone-independent breast cancer and antiest rogen-stimulated endometrial tumors. We hypothesize that alterations of the PKC isozyme profile of endometrial carcinomas are similar to that of hormo ne-independent breast cancer and determine whether specific PKC isozyme alt erations 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 b lot. The relationship between PKC isozyme expression and key prognostic fac tors for endometrial carcinoma including hormone receptor status, tumor gra de, stage, size, and depth of myometrial invasion was examined using the Sp earman's rho correlation coefficient. Results. As previously found in breast cancers, PKC alpha and estrogen rece ptor alpha (ER alpha) expression are inversely related (r(s) = -0.35, P = 0 .046). We report significant inverse correlations among ER/progesterone rec eptor (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 P KC isozyme expression and other key prognostic factors examined. Conclusion. This study indicates that, similar to what was previously obser ved in breast cancer, PKC alpha and ER expression is inversely related in e ndometrial cancer. PKC alpha expression may be a useful prognostic indicato r in endometrial cancers. A model is offered which describes the putative r ole of PKC alpha overexpression in activation of the AP-1 pathway and incre ased proliferation of ER negative endometrial cancers. (C) 2001 Academic Pr ess.