Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer.
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Date
2016-06-01Author
Simigdala, N
Gao, Q
Pancholi, S
Roberg-Larsen, H
Zvelebil, M
Ribas, R
Folkerd, E
Thompson, A
Bhamra, A
Dowsett, M
Martin, L-A
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: Therapies targeting estrogenic stimulation in estrogen receptor-positive (ER+) breast cancer (BC) reduce mortality, but resistance remains a major clinical problem. Molecular studies have shown few high-frequency mutations to be associated with endocrine resistance. In contrast, expression profiling of primary ER+ BC samples has identified several promising signatures/networks for targeting. METHODS: To identify common adaptive mechanisms associated with resistance to aromatase inhibitors (AIs), we assessed changes in global gene expression during adaptation to long-term estrogen deprivation (LTED) in a panel of ER+ BC cell lines cultured in 2D on plastic (MCF7, T47D, HCC1428, SUM44 and ZR75.1) or in 3D on collagen (MCF7) to model the stromal compartment. Furthermore, dimethyl labelling followed by LC-MS/MS was used to assess global changes in protein abundance. The role of target genes/proteins on proliferation, ER-mediated transcription and recruitment of ER to target gene promoters was analysed. RESULTS: The cholesterol biosynthesis pathway was the common upregulated pathway in the ER+ LTED but not the ER- LTED cell lines, suggesting a potential mechanism dependent on continued ER expression. Targeting the individual genes of the cholesterol biosynthesis pathway with siRNAs caused a 30-50 % drop in proliferation. Further analysis showed increased expression of 25-hydroxycholesterol (HC) in the MCF7 LTED cells. Exogenous 25-HC or 27-HC increased ER-mediated transcription and expression of the endogenous estrogen-regulated gene TFF1 in ER+ LTED cells but not in the ER- LTED cells. Additionally, recruitment of the ER and CREB-binding protein (CBP) to the TFF1 and GREB1 promoters was increased upon treatment with 25-HC and 27-HC. In-silico analysis of two independent studies of primary ER+ BC patients treated with neoadjuvant AIs showed that increased expression of MSMO1, EBP, LBR and SQLE enzymes, required for cholesterol synthesis and increased in our in-vitro models, was significantly associated with poor response to endocrine therapy. CONCLUSION: Taken together, these data provide support for the role of cholesterol biosynthesis enzymes and the cholesterol metabolites, 25-HC and 27-HC, in a novel mechanism of resistance to endocrine therapy in ER+ BC that has potential as a therapeutic target.
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Subject
Cell Line, Tumor
Humans
Breast Neoplasms
Cholesterol
Cholesterol Esters
Proteome
Receptors, Estrogen
Antineoplastic Agents, Hormonal
Estrogens
Prognosis
Treatment Outcome
Gene Expression Profiling
Proteomics
Cell Proliferation
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
RNA Interference
Drug Resistance, Neoplasm
Phenotype
Female
Biosynthetic Pathways
Transcriptome
Biomarkers
Research team
Endocrinology
Language
eng
Date accepted
2016-04-26
License start date
2016-06
Citation
Breast cancer research : BCR, 2016, 18 (1), pp. 58 - ?
Publisher
BMC