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| Status |
Public on May 20, 2016 |
| Title |
Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor positive breast cancer |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
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. In this study, the cholesterol biosynthesis pathway was the common upregulated pathway in the ER+ LTED but not 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-negative LTED. Additionally, recruitment of the ER and CREB-binding protein (CBP) to the TFF1 promoter was increased upon treatment with 25-HC and 27-HC. In silico analysis of 704 primary ER+ BC patients treated with adjuvant tamoxifen showed increased expression of MSMO1 (p=0.047), EBP (p=0.043), SQLE (p=0.000009), and IDI1 (p=0.0005), enzymes required for cholesterol synthesis and increased in our in vitro models of endocrine resistance, to be associated with poor relapse-free survival. In contrast, no association was identified in over 700 patients with ER-negative BC. 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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| Overall design |
To identify common adaptive mechanisms associated with resistance to aromatase inhibitors (AI), 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 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
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| Contributor(s) |
Gao Q |
| Citation(s) |
27246191 |
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| Submission date |
Dec 14, 2015 |
| Last update date |
Aug 13, 2018 |
| Contact name |
Alice Gao |
| E-mail(s) |
alice.gao@icr.ac.uk
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| Organization name |
The Institute of Cancer Research
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| Department |
Breast Cancer Now
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| Lab |
Molecular Cell Biology
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| Street address |
237 Fulham Road
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| City |
London |
| State/province |
London |
| ZIP/Postal code |
SW3 6JB |
| Country |
United Kingdom |
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| Platforms (1) |
| GPL10558 |
Illumina HumanHT-12 V4.0 expression beadchip |
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| Samples (54)
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| Relations |
| BioProject |
PRJNA305878 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE75971_RAW.tar |
26.2 Mb |
(http)(custom) |
TAR |
| GSE75971_non_normalized.txt.gz |
19.7 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
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