Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.
Date
2018-08-01Author
Simigdala, N
Pancholi, S
Ribas, R
Folkerd, E
Liccardi, G
Nikitorowicz-Buniak, J
Johnston, SR
Dowsett, M
Martin, L-A
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
Humans
Breast Neoplasms
Neoplasms, Hormone-Dependent
Neoplasm Metastasis
Neoplasm Recurrence, Local
Tamoxifen
Androstenes
Receptors, Androgen
Estrogen Receptor alpha
Aromatase Inhibitors
Signal Transduction
Apoptosis
Cell Proliferation
Gene Expression Regulation, Neoplastic
Drug Resistance, Neoplasm
Mutation
Female
MCF-7 Cells
Research team
Endocrine Therapy Resistance
Endocrinology
Language
eng
Date accepted
2018-05-31
License start date
2018-08
Citation
British journal of cancer, 2018, 119 (3), pp. 313 - 322
Publisher
SPRINGERNATURE
Except where otherwise noted, this item's license is described
as
https://creativecommons.org/licenses/by/4.0
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