dc.contributor.author | Simigdala, N | |
dc.contributor.author | Gao, Q | |
dc.contributor.author | Pancholi, S | |
dc.contributor.author | Roberg-Larsen, H | |
dc.contributor.author | Zvelebil, M | |
dc.contributor.author | Ribas, R | |
dc.contributor.author | Folkerd, E | |
dc.contributor.author | Thompson, A | |
dc.contributor.author | Bhamra, A | |
dc.contributor.author | Dowsett, M | |
dc.contributor.author | Martin, L-A | |
dc.date.accessioned | 2017-03-01T11:16:13Z | |
dc.date.issued | 2016-06-01 | |
dc.identifier.citation | Breast cancer research : BCR, 2016, 18 (1), pp. 58 - ? | |
dc.identifier.issn | 1465-5411 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/414 | |
dc.identifier.eissn | 1465-542X | |
dc.identifier.doi | 10.1186/s13058-016-0713-5 | |
dc.description.abstract | 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. | |
dc.format | Electronic | |
dc.format.extent | 58 - ? | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | BMC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Humans | |
dc.subject | Breast Neoplasms | |
dc.subject | Cholesterol | |
dc.subject | Cholesterol Esters | |
dc.subject | Proteome | |
dc.subject | Receptors, Estrogen | |
dc.subject | Antineoplastic Agents, Hormonal | |
dc.subject | Estrogens | |
dc.subject | Prognosis | |
dc.subject | Treatment Outcome | |
dc.subject | Gene Expression Profiling | |
dc.subject | Proteomics | |
dc.subject | Cell Proliferation | |
dc.subject | Gene Expression Regulation, Enzymologic | |
dc.subject | Gene Expression Regulation, Neoplastic | |
dc.subject | RNA Interference | |
dc.subject | Drug Resistance, Neoplasm | |
dc.subject | Phenotype | |
dc.subject | Female | |
dc.subject | Biosynthetic Pathways | |
dc.subject | Transcriptome | |
dc.subject | Biomarkers | |
dc.title | Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2016-04-26 | |
rioxxterms.versionofrecord | 10.1186/s13058-016-0713-5 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2016-06 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Breast cancer research : BCR | |
pubs.issue | 1 | |
pubs.notes | No embargo | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Endocrinology/Endocrinology (hon.) | |
pubs.publication-status | Published | |
pubs.volume | 18 | |
pubs.embargo.terms | No embargo | |
icr.researchteam | Endocrinology | |
dc.contributor.icrauthor | Gao, Qiong | |
dc.contributor.icrauthor | Pancholi, Sunil | |
dc.contributor.icrauthor | Folkerd, Elizabeth | |
dc.contributor.icrauthor | Martin, Lesley-Ann | |