The effects of various SERMs on the intracellular localization and the transactivation of estrogen receptor alpha

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-379
Toshihiro Horiuchi*, Hisaya Kawate, Mika Gushima, Masahiro Adachi, Keizo Ohnaka, Masatoshi Nomura and Ryoichi Takayanagi
Kyushu Univ, Fukuoka, Japan
‹Background›Selective estrogen receptor modulators (SERMs) bind to the estrogen receptor (ER) and act as agonists in some tissues, and as antagonists in others. At present, in Japan, three SERMs are clinically available. Tamoxifen (TAM) can reduce the risk of breast cancer in high-risk women and both raloxifene (RLX) and bazedoxifene can be used for the prevention and treatment of postmenopausal osteoporosis. We previously reported that RLX translocated estrogen receptor alpha (ERα) from nucleoplasm into nucleoli and strongly inhibited the ERα-mediated transactivation in breast cancer cell lines.‹Objective›We compared the ERα-mediated transactivation and the intracellular localization of ERα after treatment with three different SERMs (TAM, RLX and BZA) in various cell lines.‹Methods›To clarify the molecular mechanism underlying the tissue specificity of SERMs, we examined the intracellular localization of ERα using a green fluorescent protein (GFP)-tagged protein in culture cells from various tissues in the presence of estradiol (E2) or three SERMs. We also examined the ERα-mediated transactivation in several cells by functional promoter assay after treatment with E2 or three SERMs.‹Results›In MCF-7 breast cancer cells, transcriptional activation mediated by ERα was observed in the functional promoter assay in the presence of E2. However, all three SERMs strongly inhibited the ERα–mediated transactivation in MCF-7 cells. In the presence of E2, ERα showed uniform dot pattern in the nucleoplasm. On the other hand, RLX translocated almost all ERα from the nucleoplasm into the nucleoli in MCF-7 cells, whereas only small amount of ERα was observed in the nucleoli in the presence of TAM and BZA, showing heterogeneous distribution in the nucleoplasm. In uterine cancer cells (Ishikawa cells), ERα remained in the nucleoplasm in the presence of E2 and three SERMs. In the functional reporter assay, ERα-mediated transactivation can be enhanced by E2, whereas all three SERMs inhibited the transcriptional activation.‹Conclutions›RLX and BZA showed similar molecular structure and clinical outcomes. However, intracellular distribution of ERα in the presence of these SERMs was clearly different in the breast cancer cells. These results indicate that the molecular mechanism of inhibiting the ERα-mediated transactivation by RLX and BZA would be different.

Nothing to Disclose: TH, HK, MG, MA, KO, MN, RT

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