Relationship Of Hormones And Molecular Genetic Alterations

One of the defining differences between type I and type II tumors is the association of type I tumors with an estrogenic state. Despite the fact that the relationship between estrogen and Type I tumors has been recognized for several decades little is known about the molecular basis of this association. Unopposed estrogen is rarely used anymore because of this strong association; however, tamoxifen use has increased and is currently the most widely prescribed hormonal therapy for the treatment of breast cancer. Although tamoxifen has an antiestrogenic effect in the breast, it has weak estrogenic effects on the endometrium. Many epidemiological as well as randomized prospective trials have shown a moderately increased risk of endometrial cancer in association with prolonged tamoxifen treatment with relative risks ranging from 2.53 to 7.5 (25-27). Thus, two recent studies have been done to determine the molecular profiles of tamoxifen associated tumors in the hope of providing insight into the mechanisms through which estrogen contributes to endometrial carcinoma development. A gene profiling study has found that the expression patterns of the tumors were associated most closely with tumor grade and were not associated with the presence or absence of tamoxifen exposure. In addition, a molecular genetic analysis of the most common genetic alterations in endometrial carcinoma, as discussed earlier, found no difference in the frequency of mutation between the two groups of tumors (Table 1).

These studies suggest that the mechanism by which tamoxifen increases the incidence of endometrial carcinoma is through the same pathogenetic pathways that give rise to sporadic cancer. Given these results, tamoxifen may act as an initiator of tumori-genesis through estrogen agonistic activity in the endometrium, according to the suggestions made by clinical trials and laboratory studies (26,28-32). An immunohistochemical study of endometrial epithelial proliferation in postmenopausal women showed increased staining with MIB-1 in tamoxifen-exposed benign endometrium compared to nonexposed endometrium. This further supports the idea that tamoxifen exposure results in increased epithelial proliferation (29). Thus, tamoxifen may act to increase the proliferation of a subset of cells, thereby increasing the likelihood of mutations.

Alternatively, it may promote the growth of cells that have already sustained mutations thereby enhancing the ability of "occult" malignancies to develop. As a result of either or both possibilities, tamoxifen exposure could lead to the production of a spectrum of mutations similar to that of sporadic endometrial cancers at the same time explaining the observation of an increased incidence of endometrial carcinoma in this clinical setting.

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