Aromatase and comparative response to its inhibitors in two types of endometrial cancer.

Aromatase activity (AA) was evaluated totally in 80 tumors collected from primary endometrial cancer (EC) patients. All patients were divided into cases belonging to the types I or II of EC (respectively, 50 and 30 observations). Samples of malignant endometrium from type II demonstrated inclination to the higher AA in comparison with type I samples; the difference reached level of statistical significance in non-smoking patients (p=0.02). Although no positive correlation was revealed between AA in EC tissue and percentage of cells with DNA damage in normal endometrium from the same patients, the rate of DNA damage (percent of comets, comet's tail average length, etc.) was higher in intact endometrium collected from patients with type II of the disease. In 19 tumor samples, CYP19 gene expression was evaluated by RT-PCR and level of mRNA signal demonstrated positive correlation with AA (R(s)=+0.63, p=0.05) in the whole this material. Of note, though, CYP19 mRNA expression was not revealed in six cases, and all of them belonged to the type I of disease. Finally, in 23 EC patients (15 with type I and 8 with type II of the disease) effects of 2 weeks treatment with letrozole (10 pts) and exemestane (13 pts) were evaluated in neoadjuvant setting. Although diminishing of endometrial M-echo signal and the increases in FSH and LH concentration after treatment were more pronounced in type I patients, decrease in tumor PR content (p=0.04) was more revealing in patients with type II of EC; besides, the decreases in AA in tumor tissue by the end of treatment were noted predominantly in patients with lower body weight (BMI <27.5). Thus, although type II of EC is frequently considered as hormone-independent, increased ability of this type of the tumor to estrogen biosynthesis (at CYP19 gene and protein level) may lead to the reconsideration of such conclusion and warrants further investigation. The search of possible ethnic differences in AA and in the biologic response to aromatase inhibitors in EC can be of importance too.

CYP19 gene expression and aromatase activity in endometrial cancer tissue: importance of the type of the disease.

Aromatase (CYP19) activity in malignant endometrium presents local mechanism with potential ability to support tumor growth. The data on interrelation between activity of this enzyme and its mRNA signal in endometrial cancer (EC) tissue are very scarce and inconclusive. To correct this gap we studied aromatase activity and gene expression totally in 19 samples of EC (17 of them -- from postmenopausal women) collected during surgery. Aromatase activity was evaluated by tritium water release assay and CYP19 gene expression -- with rt-PCR. Additionally, all studied EC cases were divided on the basis of case history and some characteristics of host and tumor and in accordance with existing classification into cases belonging to type I or II of the disease (correspondingly, 13 and 6 observations). Positive correlation between enzyme activity and CYP19 mRNA signal (R(s)=+0.63, p<0.05) was revealed in the whole group of studied samples. Aromatase activity varied in evaluated material between 1.45 fM/mg prot./hr and 11.49 fM/mg prot./hr, and in type II cases it was higher (7.27+/-0.96 fM/mg prot/hr) than in type I observations (4.96+/-0.66 fM/mg prot./hr, p=0.066). CYP19 mRNA expression was not revealed in 6 cases and all of them belonged to the type I of disease. Thus, although type II of EC is frequently considered as hormone non-dependent, increased ability of this tumor type to estrogen biosynthesis (on CYP19 gene and protein level) may lead to reconsideration of such conclusion and warrants further investigation.

Tumor estrogen content and clinico-morphological and endocrine features of endometrial cancer.

OBJECTIVES: To compare estrogen concentrations in endometrial cancer tissue with those in macroscopically normal endometrium and with certain morphological characteristics of the tumor and endocrine parameters in patients. METHODS: The estradiol content was evaluated by radioimmunoassay after homogenization and extraction in 78 adenocarcinomas (61 from postmenopausal patients). RESULTS: Higher concentrations of estradiol in tumor tissue samples than in macroscopically normal endometrium were found in patients of both reproductive and postmenopausal age. This difference was the same in patients with either endometrial carcinoma type I or type II. No association between tumor steroid receptor levels, estradiol concentrations in blood serum, and timing of menopause with intratumoral estradiol contents was discovered. Estradiol concentrations in tumor tissues correlated positively with the clinical stage of disease and rate of tumor invasion (in patients with peripheric/lower type of fat topography), and negatively with tumor differentiation stage (in patients with central/upper type of fat topography) and the percentage of intact double-stranded DNA in normal endometrium. CONCLUSIONS: Tumor estrogen content in endometrial cancer has clinical significance that is modified in the presence of certain endocrine characteristics related to insulin resistance. The role of local estrogen production (aromatase activity) in this setting deserves special study.

CYP19 gene polymorphism in endometrial cancer patients.

PURPOSE: Initiation/promotion of endometrial cancer is known to be associated with estrogenic influence. Therefore, it is possible that some allelic polymorphisms of the genes involved in steroidogenesis or steroid metabolism contribute to endometrial cancer susceptibility. METHODS: Here, we compared CYP19 (aromatase) gene polymorphism in 85 endometrial cancer patients and in 110 non-affected women. RESULTS: The genotypes containing the longest alleles (A6 and A7) of CYP19 were found to be over-represented in patients as compared to controls. In addition, these genotypes demonstrated a tendency to be associated with increased concentrations of estradiol and testosterone in postmenopausal patients. CONCLUSIONS: Thus, CYP19 polymorphism might be one of the genetic risk factors for endometrial cancer development.