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.
|Number of pages||1|
|Publication status||Published - 2014|
|Event||ASCEPT-MPGCR Joint Scientific Meeting - Melbourne Convention & Exhibition Centre, Melbourne, Australia|
Duration: 7 Dec 2014 → 11 Dec 2014
|Conference||ASCEPT-MPGCR Joint Scientific Meeting|
|Period||7/12/14 → 11/12/14|
- breast carcinogenesis
- testosterone-glucuronidating activity
Chanawong, A., Hu, D. G., Meech, R., McKinnon, R., & Mackenzie, P. (2014). 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. 10-10. Abstract from ASCEPT-MPGCR Joint Scientific Meeting, Melbourne, Australia.