title: Tamoxifen regulates human telomerase reverse transcriptase (hTERT) gene expression differently in breast and endometrial cancer cells.
abstract: Tamoxifen is widely applied as an antiestrogenic agent for adjuvant therapy in the treatment of breast cancer, while its estrogen-agonistic activity occasionally causes proliferative disorders or carcinogenesis at other sites, such as the uterus. We reported that estrogen activates telomerase in breast and endometrial cancer cells. The present study examines the effects of tamoxifen on the gene expression of human telomerase reverse transcriptase (hTERT) in breast and endometrial cancer cells. Tamoxifen inhibited the cell growth of MCF-7 cells, as well as hTERT mRNA expression in the presence of estrogen (E2), antagonizing the E2 effects. In contrast, tamoxifen stimulated the growth of Ishikawa cells and activated hTERT mRNA expression in the absence or presence of E2, exhibiting estrogen-agonistic action. Transient expression assays revealed that these actions of tamoxifen are achieved by transcriptional regulation of the hTERT promoter. An estrogen responsive element (ERE) in the hTERT 5' regulatory region was partly responsible for both the E2-antagonistic and -agonistic actions of tamoxifen. Tamoxifen activated the MAP kinase cascade in Ishikawa cells, but not in MCF-7 cells, and the activation of hTERT mRNA expression was effectively blocked by MEK inhibitor, suggesting that the MAP kinase pathway is involved in the tamoxifen-induced activation of hTERT. These findings indicate that tamoxifen regulates hTERT expression in a cell-type specific manner. Tamoxifen-induced activation of hTERT may be one component of estrogen agonistic function of tamoxifen that is involved in endometrial carcinogenesis induced by this agent.
authors.affiliation: Department of Obstetrics and Gynecology, Kanazawa University, School of Medicine, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Wang
authors.forename: Satoru
authors.initials: S
authors.lastname: Kyo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Maida
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takakura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tanaka
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Yatabe
authors.forename: Taro
authors.initials: T
authors.lastname: Kanaya
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Nakamura
authors.forename: Koji
authors.initials: K
authors.lastname: Koike
authors.forename: Koji
authors.initials: K
authors.lastname: Hisamoto
authors.forename: Masahide
authors.initials: M
authors.lastname: Ohmichi
authors.forename: Masaki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D024506:5' Flanking Region; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins; D016889:Endometrial Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004958:Estradiol / Q000819:agonists; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System; D009928:Organ Specificity; D012334:RNA, Neoplasm / Q000096:biosynthesis; D020218:Response Elements; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D018931:Antineoplastic Agents, Hormonal; D004268:DNA-Binding Proteins; D004965:Estrogen Antagonists; D012334:RNA, Neoplasm; D020845:Selective Estrogen Receptor Modulators; D018808:Transcription Factor AP-1; D013629:Tamoxifen; D004958:Estradiol; D019098:Telomerase