Biological Roles of Estrogen and Progesterone in Human Endometrial Carcinoma - New developments in potential endocrine therapy for endometrial cancer -

Abstract

Abstract. Endometrial carcinoma is one of the most common female pelvic malignancies. It is well known that uterine endometrial cell proliferation is under the control of both estrogen and progesterone. In this review, results of the recent studies on the biosynthesis and action of estrogen and progestin in normal endometrium and its disorders will be summarized and the new aspects of hormonal therapies in the patients with endometrial carcinoma will be discussed including its future prospectives. We reported that the enzymes responsible for intratumoral estrogen metabolism and biosynthesis are markedly different between human breast and endometrial carcinoma, although both of them are considered "estrogen-dependent malignancies". In addition, the biological significance of Progesterone receptor (PR) isoforms is considered to differ between endometrial and breast carcinomas. Clinical data concerning Hormone replacement therapy (HRT) and estrogen-dependent cancer risk also support these findings. These basic and clinical findings help to understand the biology and provide the new knowledge for prevention, diagnosis and treatment of human endomerial carcinoma. Specific endocrine treatment of endometrial carcinoma should be explored in future, although aromatase inhibitors are the most effective endocrine treatments of estrogen-responsive breast carcinoma. Retinoid, metabolities of vitamin A, and synthetic peroxisome proliferator-activated receptor (PPAR) γ ligands, which have been used for the treatment of insulin resistance in type II diabetes mellitus, may be the important candidates as drugs not only for prevention but also for possible endocrine treatment of endometrial carcinoma.

Autocrine stimulation of IGF1 in estrogen-induced growth of endometrial carcinoma cells: involvement of the mitogen-activated protein kinase pathway followed by up-regulation of cyclin D1 and cyclin E

“…Therefore, to our knowledge, this is the first report showing the presence of an E 2 -induced entire autocrine loop mediated by IGF1 in the cell proliferation of endometrial carcinoma cells. The E 2 concentration used in the present study (10 K6 M) is higher than that of physiological condition; however, elevated E 2 concentrations in the tumor microenvironment several times higher than that of the physiological levels have been reported (Ito et al 2007). IGF1-induced cell proliferation was half of that of E 2 -induced in this The expression of pMAPK both in the cytoplasm and nucleus was increased in the normal proliferative phase endometrium and endometrial carcinoma compared with that in the secretory phase endometria (P!0.05).…”

Improved survival related to changes in endometrial cancer treatment, a 30-year population based perspective

“…When progesterone is added in the second half of the menstrual cycle, the estrogen driven proliferation is antagonized and the epithelium differentiates from the proliferative to the secretory phase. 134 Although both estrogen and progesterone receptor status is known to correlate with clinical features and prognosis in both endometrial and breast cancer, targeting the ER pathway yields partly different results for these cancers. 135 …”

“…138 PR PR is considered essential to inhibit estrogen induced hyperproliferation, and thus to counteract carcinogenesis. Both PR-A and PR-B are expressed in endometrial tissue 134 , but in endometrial cancer mostly PR-A is investigated and generally referred to as PR. Similarly to ER, PR loss is correlated with Type II cancers.…”

“…138 Progestin effects are mainly mediated through PR, and in ER positive tumours progestin may yield an anti-estrogen effect. 134 This treatment option is mainly considered as a possibility for young women with endometrioid low grade tumours where removal of the uterus is avoided to retain the possibility of child-bearing.…”

Biomarkers as prognostic factors in endometrial cancer.

“…Additionally, it is thought that the ER and PR status constitutes independent prognostic factors [28]. However, PR, in contrast to ER, is suggested to be a more predictive factor of disease-free survival [29], while some authors have also reported that the presence of steroid receptors does not constitute an independent prognostic factor for endometrial cancer [30].…”