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Cited by 79Cancer, Lipids, and MetabolismCholesterol and Lipid MetabolismBreast Cancer Treatment Studies

High expression of cholesterol biosynthesis genes is associated with resistance to statin treatment and inferior survival in breast cancer

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Kimbung, Siker, Lettiero, Barbara, Feldt, Maria, Bosch, Ana, Borgquist, Signe·2016·Oncotarget
DOI 10.18632/oncotarget.10746PMC PMC5312337
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Abstract

// Siker Kimbung 1 , Barbara Lettiero 1 , Maria Feldt 1 , Ana Bosch 1, 2 , Signe Borgquist 1, 2 1 Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden 2 Department of Oncology, Skåne University Hospital, Lund, Sweden Correspondence to: Siker Kimbung, email: Siker.kimbung@med.lu.se Signe Borgquist, email: Signe.borgquist@med.lu.se Keywords: statin, breast cancer, cholesterol biosynthesis, predictive biomarker, prognosis Received: April 12, 2016 Accepted: July 10, 2016 Published: July 21, 2016 ABSTRACT There is sufficient evidence that statins have a protective role against breast cancer proliferation and recurrence, but treatment predictive biomarkers are lacking. Breast cancer cell lines displaying diverse sensitivity to atorvastatin were subjected to global transcriptional profiling and genes significantly altered by statin treatment were identified. Atorvastatin treatment strongly inhibited proliferation in estrogen receptor (ER) negative cell lines and a commensurate response was also evident on the genome-wide transcriptional scale, with ER negative cells displaying a robust deregulation of genes involved in the regulation of cell cycle progression and apoptosis. Interestingly, atorvastatin upregulated genes involved in the cholesterol biosynthesis pathway in all cell lines, irrespective of sensitivity to statin treatment. However, the level of pathway induction; measured as the fold change in transcript levels, was inversely correlated to the effect of statin treatment on cell growth. High expression of cholesterol biosynthesis genes before treatment was associated with resistance to statin therapy in cell lines and clinical biopsies. Furthermore, high expression of cholesterol biosynthesis genes was independently prognostic for a shorter recurrence-free and overall survival, especially among ER positive tumors. Dysregulation of cholesterol biosynthesis is therefore predictive for both sensitivity to anti-cancer statin therapy and prognosis following primary breast cancer diagnosis.

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  • Statins have high first-pass metabolism, allowing tumors to escape and produce their own cholesterol.

    “However, statins have a high first-pass metabolism, allowing for tumors to escape and produce their own cholesterol (11, 12).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [12]

    The Discussion (page unavailable) says most orally administered statins are unlikely to reach the concentrations used in vitro outside the liver. It also reports that less-sensitive breast cancer cells strongly induced cholesterol-biosynthesis genes after statin treatment. The paper does not establish high first-pass metabolism or show that it allows tumors to escape treatment by producing their own cholesterol. (LLM, conf=0.84)

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Cited by

Sorted by citations

Authors
Kimbung, S., Lettiero, B., Feldt, M., Bosch, A., & Borgquist, S.
Affiliations
Lund University (SE)
ORCID
Venue
Oncotarget
Publisher
Impact Journals, LLC
Published
2016-07-21
Volume
7
Issue
37
Pages
59640-59651
ISSN
1949-2553 (ISSN-L)
DOI
10.18632/oncotarget.10746
PMC
PMC5312337
OpenAlex
W2502178910
Cited by
79
References
1
Citations by year
2026: 2 · 2025: 6 · 2024: 5 · 2023: 8 · 2022: 20 · 2021: 7 · 2020: 11 · 2019: 10 · 2018: 7 · 2017: 3
FWCI
2.78
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Oncotarget (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
Funders
  • Swedish Cancer Foundation
  • Vetenskapsrådet
  • Fru Berta Kamprads Stiftelse
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
breast cancer, cholesterol biosynthesis, statin resistance, atorvastatin, predictive biomarkers, prognostic factors, estrogen receptor status, gene expression profiling, cell cycle regulation, apoptosis, recurrence-free survival, overall survival
MeSH terms
Atorvastatin, Breast Neoplasms, Cell Cycle, Cholesterol, Female, Humans, Receptors, Estrogen, Gene Expression Regulation, Neoplastic, Survival Analysis, Apoptosis, Drug Resistance, Neoplasm, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Gene Expression Profiling, Cell Line, Tumor, Biosynthetic Pathways, MCF-7 Cells

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