Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-08

AUTHORS

Nikiana Simigdala, Sunil Pancholi, Ricardo Ribas, Elizabeth Folkerd, Gianmaria Liccardi, Joanna Nikitorowicz-Buniak, Stephen R. Johnston, Mitch Dowsett, Lesley-Ann Martin

ABSTRACT

BACKGROUND: Resistance to endocrine therapy remains a major clinical problem in the treatment of oestrogen-receptor positive (ER+) breast cancer. Studies show androgen-receptor (AR) remains present in 80-90% of metastatic breast cancers providing support for blockade of AR-signalling. However, clinical studies with abiraterone, which blocks cytochrome P450 17A1 (CYP17A1) showed limited benefit. METHODS: In order to address this, we assessed the impact of abiraterone on cell-viability, cell-death, ER-mediated transactivation and recruitment to target promoters. together with ligand-binding assays in a panel of ER+ breast cancer cell lines that were either oestrogen-dependent, modelling endocrine-sensitive disease, or oestrogen-independent modelling relapse on an aromatase inhibitor. The latter, harboured wild-type (wt) or naturally occurring ESR1 mutations. RESULTS: Similar to oestrogen, abiraterone showed paradoxical impact on proliferation by stimulating cell growth or death, depending on whether the cells are hormone-dependent or have undergone prolonged oestrogen-deprivation, respectively. Abiraterone increased ER-turnover, induced ER-mediated transactivation and ER-degradation via the proteasome. CONCLUSIONS: Our study confirms the oestrogenic activity of abiraterone and highlights its differential impact on cells dependent on oestrogen for their proliferation vs. those that are ligand-independent and harbour wt or mutant ESR1. These properties could impact the clinical efficacy of abiraterone in breast cancer. More... »

PAGES

313-322

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41416-018-0158-y

    DOI

    http://dx.doi.org/10.1038/s41416-018-0158-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1105180670

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29991699


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