Tamoxifen modulates apoptotic pathways in primary endometrial cell cultures.

Clinical data indicate that tamoxifen (TAM) therapy may cause an increased risk of endometrial pathology in postmenopausal but not in premenopausal women. Molecular mechanisms of the uterotrophic activity of TAM have not been clearly established nor its relevance to apoptosis in endometrial cells. The present study was implemented to evaluate the apoptotic effect of TAM on primary endometrial cell cultures in the presence or absence of steroid hormones (SHs). A total of 14 primary endometrial cell cultures were established and maintained both with and without SHs. Cell cultures were treated for 24 h with either 20 microM TAM or 10 nM estradiol. Apoptotic cells presented in a pre-G1 peak and the expression of bcl-2 were studied using flow cytometry. All endometrial cell cultures maintained in a SH-containing environment, except one, responded to TAM by a significant increase (P = 0.03) in the pre-G1 cell fraction, indicating a proapoptotic effect. A significant (P = 0.03) reduction in the pre-G1 peak equivalent to an antiapoptotic response was observed in 6 of 13 cell cultures maintained in a SH-deficient environment. In 4 of 10 cell cultures evaluated in both media, the pre-G1 population was medium dependent. In 8 of 10 cultures evaluated for Bcl2 levels, no trend was found in either media, but a dependency on SH content was observed. Comparison between effects of TAM and estradiol demonstrated identical trends, regardless of the menstrual phase or SH content in cell environments. These results suggest that TAM acts as an estrogen agonist on endometrial tissue in both environments. We conclude that TAM modulates apoptotic pathways in primary endometrial cell cultures. The SH content in the cell environment influences the apoptotic effect of TAM and determines the propensity for a cell to undergo apoptosis or, on the contrary, to resist apoptotic death in response to TAM treatment. This is in concordance with the observed clinical risk of endometrial pathologies in postmenopausal versus premenopausal women.

Adenomatous polyposis coli I1307K mutation in Jewish patients with different ethnicity: prevalence and phenotype.

BACKGROUND: A new mutation, I1307K, recently was reported in the adenomatous polyposis coli (APC) gene. This mutation was found to be predominant in Ashkenazi Jews, creating a hypermutable area and predisposing the development of carcinoma. The objective of the current study was to estimate the prevalence of this mutation in several of the ethnic groups that comprise the Israeli population and to elucidate the clinical features of the mutation carriers with colorectal carcinoma (CRC). METHODS: A total of 111 consecutive CRC patients were evaluated and their medical history and clinical data recorded. The general population (298 Ashkenazim and 189 Yemenites) also was tested for the presence of this mutation. Mutation screening was performed using both the polymerase chain reaction-based amplification refractory mutation system and a commercial APC kit. RESULTS: Of the total of 111 CRC patients, 15 (13.5%) carried the I1307K mutation and 26 of 487 subjects from the general population (5.3%) carried the I1307K mutation (P = 0.004). Among the 71 Ashkenazi CRC patients there were 12 carriers (16.9%) whereas 17 of the 298 Ashkenazi Jewish general population (5.7%) carried the mutation (P = 0.004). Of the 4 CRC patients of Yemenite origin, 3 carried the mutation and 9 carriers were found among 189 subjects in the general Yemenite population (4.7%) (P = 0.0007). None of the 34 Sepharadic or 2 Arab CRC patients carried the APC I1307K allele. Late age at diagnosis (64.6 years +/- 10.0, which is similar to that of the noncarriers), mostly right-sided tumors, and moderate to good differentiation constituted the phenotype of the mutation carriers. CONCLUSIONS: The authors believe the findings of the current study broaden the known spectrum of ethnic groups in which the APC I1307K mutation is prevalent. The phenotype of the mutation carrier CRC patients does not conform to the expected familial pattern of germline mutations. The phenotype and the differential incidence rate of CRC among APC I1307K carriers of various ethnic groups suggest low penetrance.