title: In vivo and in vitro estrogenic and progestagenic actions of Tibolone.
abstract: Estrogen and progestin combination in hormone replacement therapy (HRT) increases the incidence of breast cancer, but decreases the endometrial cancer risk of unopposed estrogen. Therefore, a SERM such as Tibolone, that delivers the beneficial, but not the adverse side effects, of steroid hormones would be clinically advantageous. However, data from the Million Women Study suggests that Tibolone increases the risk of both breast and endometrial cancer. Herein, we assessed the estrogenic and progestagenic actions of Tibolone using transvaginal sonography studies and an in vitro model of breast (ZR-75, MCF7) and endometrial cancer (Ishikawa). The known cancer associated proteins (ER, EGFR, STATS, tissue factor and Bcl-xL) were selected for study. Transvaginal sonography demonstrated that postmenopausal women treated with Tibolone displayed a thinner endometrium than in the late proliferative phase, but had a phenotype characteristic of the secretory phase, thus demonstrating the estrogenic and progestagenic actions of this SERM. In vitro, Tibolone acted as an estrogen in downregulating ER and upregulating Bcl-xL, yet as progesterone, increasing STAT5 and tissue factor in breast cancer cells. The increase in tissue factor by Tibolone correlated with its coagulative potential. Interestingly, EGFR was up-regulated by progesterone in the breast and by estrogen in endometrial cells, while Tibolone increased protein levels in both cell types. In conclusion, this study further demonstrates the estrogenic and progestagenic nature of Tibolone. The pattern of regulation of known oncogenes in cells of breast and endometrial origin dictates caution and vigilance in the prescription of Tibolone and subsequent patient monitoring.
authors.affiliation: Unidad de Reproducción y Desarrollo, Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Alameda 340, Santiago, Chile.
authors.forename: Anil
authors.initials: A
authors.lastname: Sadarangani
authors.forename: Ana María
authors.initials: AM
authors.lastname: Salgado
authors.forename: Sumie
authors.initials: S
authors.lastname: Kato
authors.forename: Mauricio
authors.initials: M
authors.lastname: Pinto
authors.forename: Andrés
authors.initials: A
authors.lastname: Carvajal
authors.forename: Carolina
authors.initials: C
authors.lastname: Monso
authors.forename: Gareth I
authors.initials: GI
authors.lastname: Owen
authors.forename: Pilar
authors.initials: P
authors.lastname: Vigil
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics; D045744:Cell Line, Tumor; D016889:Endometrial Neoplasms / Q000737:chemistry / Q000235:genetics; D004717:Endometrium / Q000000981:diagnostic imaging / Q000187:drug effects*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009652:Norpregnenes / Q000494:pharmacology*; D011372:Progestins / Q000378:metabolism*; D013997:Time Factors; D014463:Ultrasonography
chemical_list: D014408:Biomarkers, Tumor; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D009652:Norpregnenes; D011372:Progestins; C027385:tibolone