Signaling by steroid hormone receptor plays a pivotal role in all stages of prostate carcinogenesis. The characteristic age-related decrease in the ratio of androgens to estrogens in men may represent a contributing factor in prostate cancer development. We recently reported (MCB 20(11):3764, 2000) that estrogens can reverse telomerase silencing in normal ovary epithelium cells, and identified the catalytic subunit of telomerase, hTERT, as a transcriptional target of estrogen receptor ??(ER?). Interestingly, the newly discovered ER? is abundantly expressed in rat and human prostate epithelium, while the ER? gene appears to be transcriptionally inactivated by DNA methylation in prostate cancer cell lines and tissue specimens. The aim of our study is to define whether altered estrogen receptor signaling contributes to telomerase reactivation during malignant transformation of prostate epithelial cells. In agreement with our previous observations, we found that treatment with 17?-estradiol (E2) increased hTERT mRNA levels and telomerase activity in human normal prostatic epithelial cells and prostate cancer cell lines. Functional reporter assays in LNCAP and DU145 prostate cancer cell lines, which express only ER?, showed that, in the presence of E2, hTERT promoter activity was significantly increased via the endogenous ER?. Mutation of the estrogen response element in the hTERT promoter abolished estrogen responsiveness. In contrast, no estrogen-dependent induction of the hTERT promoter was observed in PC3 cells that express mainly ER?. These latter findings are remarkable, since in a non-prostate cell enviroment (MCF-7, OVCA-433, MDA-MB231, NIH3T3), the estrogen responsiveness of the hTERT promoter was mediated exclusively by the ER? subtype. Mobility shift assays, using nuclear extracts from prostate cancer cell lines and from cells freshly explanted from prostatic neoplasia in situ and prostatic carcinomas, showed predominant binding of the endogenous ER? to the hTERT promoter. In conclusion, hTERT activity in human prostate cancer cells is induced by estrogens through specific activation of the ER? pathway, a finding that suggests the possibility of novel hormonal therapeutic approaches in prostate cancer.
ESTROGEN RECEPTOR BETA MEDIATES INDUCTION OF TELOMERASE ACTIVITY IN HUMAN PROSTATE CANCER.
F Moretti;A Farsetti
2001
Abstract
Signaling by steroid hormone receptor plays a pivotal role in all stages of prostate carcinogenesis. The characteristic age-related decrease in the ratio of androgens to estrogens in men may represent a contributing factor in prostate cancer development. We recently reported (MCB 20(11):3764, 2000) that estrogens can reverse telomerase silencing in normal ovary epithelium cells, and identified the catalytic subunit of telomerase, hTERT, as a transcriptional target of estrogen receptor ??(ER?). Interestingly, the newly discovered ER? is abundantly expressed in rat and human prostate epithelium, while the ER? gene appears to be transcriptionally inactivated by DNA methylation in prostate cancer cell lines and tissue specimens. The aim of our study is to define whether altered estrogen receptor signaling contributes to telomerase reactivation during malignant transformation of prostate epithelial cells. In agreement with our previous observations, we found that treatment with 17?-estradiol (E2) increased hTERT mRNA levels and telomerase activity in human normal prostatic epithelial cells and prostate cancer cell lines. Functional reporter assays in LNCAP and DU145 prostate cancer cell lines, which express only ER?, showed that, in the presence of E2, hTERT promoter activity was significantly increased via the endogenous ER?. Mutation of the estrogen response element in the hTERT promoter abolished estrogen responsiveness. In contrast, no estrogen-dependent induction of the hTERT promoter was observed in PC3 cells that express mainly ER?. These latter findings are remarkable, since in a non-prostate cell enviroment (MCF-7, OVCA-433, MDA-MB231, NIH3T3), the estrogen responsiveness of the hTERT promoter was mediated exclusively by the ER? subtype. Mobility shift assays, using nuclear extracts from prostate cancer cell lines and from cells freshly explanted from prostatic neoplasia in situ and prostatic carcinomas, showed predominant binding of the endogenous ER? to the hTERT promoter. In conclusion, hTERT activity in human prostate cancer cells is induced by estrogens through specific activation of the ER? pathway, a finding that suggests the possibility of novel hormonal therapeutic approaches in prostate cancer.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
