Abiraterone shows alternate activity in models of endocrine resistant and sensitive disease.
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Authors
Simigdala, N
Pancholi, S
Ribas, R
Folkerd, E
Liccardi, G
Nikitorowicz-Buniak, J
Johnston, SR
Dowsett, M
Martin, L-A
Pancholi, S
Ribas, R
Folkerd, E
Liccardi, G
Nikitorowicz-Buniak, J
Johnston, SR
Dowsett, M
Martin, L-A
Document Type
Journal Article
Date
2018-08-01
Date Accepted
2018-05-31
Date Available
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.
Citation
British journal of cancer, 2018, 119 (3), pp. 313 - 322
Source Title
Publisher
SPRINGERNATURE
ISSN
0007-0920
eISSN
1532-1827
Collections
Research Team
Endocrine Therapy Resistance
Endocrinology
Endocrinology