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Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer

Overview of attention for article published in Breast Cancer Research, June 2016
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About this Attention Score

  • In the top 5% of all research outputs scored by Altmetric
  • Among the highest-scoring outputs from this source (#11 of 1,605)
  • High Attention Score compared to outputs of the same age (99th percentile)
  • High Attention Score compared to outputs of the same age and source (95th percentile)

Mentioned by

news
29 news outlets
blogs
1 blog
twitter
14 tweeters
patent
1 patent
facebook
2 Facebook pages

Citations

dimensions_citation
43 Dimensions

Readers on

mendeley
83 Mendeley
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Title
Cholesterol biosynthesis pathway as a novel mechanism of resistance to estrogen deprivation in estrogen receptor-positive breast cancer
Published in
Breast Cancer Research, June 2016
DOI 10.1186/s13058-016-0713-5
Pubmed ID
Authors

Nikiana Simigdala, Qiong Gao, Sunil Pancholi, Hanne Roberg-Larsen, Marketa Zvelebil, Ricardo Ribas, Elizabeth Folkerd, Andrew Thompson, Amandeep Bhamra, Mitch Dowsett, Lesley-Ann Martin

Abstract

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. 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. 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. 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.

Twitter Demographics

The data shown below were collected from the profiles of 14 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 83 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Mexico 1 1%
United States 1 1%
Unknown 81 98%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 27 33%
Researcher 13 16%
Student > Master 10 12%
Student > Bachelor 8 10%
Student > Doctoral Student 5 6%
Other 12 14%
Unknown 8 10%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 24 29%
Medicine and Dentistry 17 20%
Agricultural and Biological Sciences 14 17%
Pharmacology, Toxicology and Pharmaceutical Science 5 6%
Chemistry 4 5%
Other 9 11%
Unknown 10 12%

Attention Score in Context

This research output has an Altmetric Attention Score of 248. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 02 February 2019.
All research outputs
#61,481
of 15,041,535 outputs
Outputs from Breast Cancer Research
#11
of 1,605 outputs
Outputs of similar age
#2,174
of 268,088 outputs
Outputs of similar age from Breast Cancer Research
#1
of 21 outputs
Altmetric has tracked 15,041,535 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 99th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,605 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.1. This one has done particularly well, scoring higher than 99% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 268,088 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 99% of its contemporaries.
We're also able to compare this research output to 21 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 95% of its contemporaries.