Tamoxifen and its active metabolite 4-hydroxytamoxifen, up-regulate UDP-glucuronosyltransferases (UGT) 2B15 and 2B17 in breast cancer cells: a novel mechanism of tamoxifen antiestrogenic activity

    Research output: Contribution to conferenceAbstract

    Abstract

    Poster abstract.Introduction. Testosterone is converted into estrogen in breast cancer cells. Hence, removal of testosterone by glucuronidation has a potential impact on estrogen-driven breast carcinogenesis and cancer progression. As the testosterone-glucuronidating UDP glucuronosyltransferases 2B15 and 2B17 are expressed in breast cells, factors that control their expression may have an important role in modulating these pro-carcinogenic estrogen effects. Aim. To study the potential regulation of UGT2B15 and 2B17 by tamoxifen and its active metabolite in breast cancer cells. Methods & Results. UGT2B15 and 2B17 mRNA levels and testosterone-glucuronidating activity weresignificantly increased in breast cancer MCF-7 cells treated with tamoxifen and 4-hydroxytamoxifen (4-OH-tamoxifen). This increase was abrogated by either knockdown of estrogen receptor Į (E5Į) by siRNA or the ER antagonist, ICI 182,780. Furthermore, tamoxifen and 4-OH-tamoxifen stimulated the activity of the UGT2B15 promoter. This stimulation was enhanced by overexpression of E5Į but significantly reduced by mutation of the previously reported functional estrogen response unit (ERU) at the UGT2B15 proximal promoter. Chromatin immunoprecipitation (ChIP) assay showed enrichment of ER binding at the ERU of the UGT2B15 promoter upon 4-OH-tamoxifen exposure. Discussion. Tamoxifen and its active metabolite up-regulate UGT2B15 and 2B17 expression via ER in breast cancer cells. This tamoxifen-induced UGT2B15 and 2B17 enzymatic activity may facilitate the removal of testosterone from tumour cells. This is a novel mechanism that may contribute to the antiestrogenic effects of tamoxifen which is used in the treatment of estrogen receptor positive breast cancers.
    Original languageEnglish
    Pages10-10
    Number of pages1
    Publication statusPublished - 2014
    EventASCEPT-MPGCR Joint Scientific Meeting - Melbourne Convention & Exhibition Centre, Melbourne, Australia
    Duration: 7 Dec 201411 Dec 2014

    Conference

    ConferenceASCEPT-MPGCR Joint Scientific Meeting
    CountryAustralia
    CityMelbourne
    Period7/12/1411/12/14

    Keywords

    • breast carcinogenesis
    • testosterone-glucuronidating activity
    • tamoxifen
    • 4-hydroxytamoxifen
    • testosterone

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