Transcriptional analysis of steroid hormone receptors in smooth muscle uterine leiomyoma tumors of postmenopausal patients.

Smooth muscle tumors are histologically separated into benign leiomyomas and malignant leiomyosarcomas. Uterine leiomyomas represent benign clonal tumors often arising within the smooth muscle tissue of the human uterus. Uterine leiomyomas develop after the start of the menstrual cycle, become symptomatic during middle age, and in most postmenopausal patients tumor regression occurs. Rarely, leiomyomas progress to leiomyosarcomas, where many sarcomas have markedly reduced or no steroid hormone receptors, thus, evolve to a hormone non-responsive state. Premenopausal leiomyomas are known to express higher levels of estrogen receptor-alpha (ERalpha), estrogen receptor-beta (ERbeta) and progesterone receptor (PGR) than control myometrium, whereas postmenopausal leiomyomas have not been so well characterized molecularly. In this present investigation, ERbeta, ERalpha and PGR gene expression were assessed in leiomyomas and in matched adjacent myometrium from a cohort of 14 postmenopausal patients using semi-quantitative Realtime PCR and RT-PCR. The mean average results showed that ERbeta was 2.5-fold statistically significantly over expressed in postmenopausal leiomyomas compared to patient matched myometrium (p=0.038), whereas ERalpha and PGR were not significantly differently expressed. These results showed that up-regulation of ERbeta occurred at the transcriptional level in postmenopausal leiomyomas. Quantitation of steroid hormone receptors from benign uterine tumors may be important for a more tailored therapy. In addition, a role for steroid hormones, specifically ERbeta, is discussed in terms of benign tumor regression or tumor maintenance in postmenopausal leiomyomas.

Proliferation and cell-cell fusion of endometrial carcinoma are induced by the human endogenous retroviral Syncytin-1 and regulated by TGF-beta.

Endometrial carcinomas (EnCa) predominantly represent a steroid hormone-driven tumor initiated from prestages. The human endogenous retrovirus HERV-W envelope gene Syncytin-1 was significantly increased at the mRNA and protein levels in EnCa and prestages compared to controls. Steroid hormone treatment of primary EnCa cells and cell lines induced Syncytin-1 due to a new HERV-W estrogen response element and resulted in increased proliferation. Activation of the cAMP-pathway also resulted in Syncytin-1 upregulation, but in contrast to proliferation, classic cell-cell fusions similar to placental syncytiotrophoblasts occurred. Cell-cell fusions were also histologically identified in endometrioid EnCa tumors in vivo. Clonogenic soft agar experiments showed that Syncytin-1 is also involved in anchorage-independent colony growth as well as in colony fusions depending on steroid hormones or cAMP-activation. The posttranscriptional silencing of Syncytin-1 gene expression and a concomitant functional block of induced cell proliferation and cell-cell fusion with siRNAs proved the essential role of Syncytin-1 in these cellular processes. TGF-beta1 and TGF-beta3 were identified as main regulative factors, due to the finding that steroid hormone inducible TGF-beta1 and TGF-beta3 inhibited cell-cell fusion, whereas antibody-mediated TGF-beta neutralization induced cell-cell fusions. These results showed that induced TGF-beta could override Syncytin-1-mediated cell-cell fusions. Interactions between Syncytin-1 and TGF-beta may contribute to the etiology of EnCa progression and also help to clarify the regulation of cell-cell fusions occurring in development and in other syncytial cell tumors.