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 (PKCalpha), 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, PKCalpha and estrogen receptor alpha (ERalpha) 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, PKCalpha and ER expression is inversely related in endometrial cancer. PKCalpha expression may be a useful prognostic indicator in endometrial cancers. A model is offered which describes the putative role of PKCalpha overexpression in activation of the AP-1 pathway and increased proliferation of ER negative endometrial cancers.

COX-2 and colon cancer: potential targets for chemoprevention.

Evidence derived from several lines of investigation suggest that prostaglandins, metabolites of arachidonic acid, play an important role in colon cancer development. Elevated prostaglandin levels are found in colon cancers and their precursor lesions, adenomatous polyps. Agents such as aspirin and NSAIDs, which inhibit the generation of these arachidonic acid metabolites, are associated with a decreased risk of developing or dying from colon cancer. Both the amount of the agent used and the duration of exposure seem to be important variables. In animals, NSAIDs are among the most potent agents discovered for the reduction of tumors in both genetic and carcinogen-induced models. Data from human trials also suggests that NSAIDs such as sulindac can reduce the size and number of polyps in individuals with familial adenomatous polyposis (FAP). In parallel with the above findings, it is now understood that at least two forms of the enzyme responsible for the metabolism of arachidonic acid exist. One of these forms, COX-1, is generally considered a constitutive form that is responsible for maintaining normal physiologic function. Inhibition of COX-1 leads to many of the clinically undesirable side effects associated with NSAID use. The other known form of the enzyme, COX-2, is an inducible form that is found in increased levels in inflammatory states and in many cancers and their associated pre-malignant lesions. Levels of COX-2 are increased by exposure to mitogens and growth factors. Agents that specifically inhibit COX-2 are now in clinical development and appear to be well-tolerated and effective for the treatment of osteoarthritis and rheumatoid arthritis. The potential for use of COX-2 specific NSAIDs in the prevention of colon cancer is suggested from the distribution of COX-2 in adenomatous polyps and colon cancer and the effectiveness of these agents in genetic and carcinogen-induced animal models of colon cancer. The development of these agents for the prevention of colon cancer will be discussed.