Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome

Sidse Ehmsen, Martin H. Pedersen, Guisong Wang, Mikkel G. Terp, Amina Arslanagic, Brian L. Hood, Thomas P. Conrads, Rikke Leth-Larsen, Henrik J. Ditzel*

*Corresponding author for this work

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Abstract

Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer. Ehmsen et al. identify cholesterol biosynthesis as essential for breast cancer stem cell propagation. Increased expression of multiple cholesterol biosynthesis proteins is observed in mammospheres, and the expression levels of these proteins correlate with the outcome of basal-like breast cancer patients. Inhibition of the cholesterol biosynthesis pathway reduces mammosphere formation.

Original languageEnglish
JournalCell Reports
Volume27
Issue number13
Pages (from-to)3927-3938.e6
ISSN2211-1247
DOIs
Publication statusPublished - 25. Jun 2019

Fingerprint

Biosynthesis
Stem cells
Cholesterol
Tumors
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Neoplasms
Proteins
Metabolites
RNA Interference
Heterografts
Tissue

Keywords

  • breast cancer stem cells
  • cholesterol biosynthesis pathway
  • mammospheres
  • PDX tumors
  • proteome profiling

Cite this

Ehmsen, Sidse ; Pedersen, Martin H. ; Wang, Guisong ; Terp, Mikkel G. ; Arslanagic, Amina ; Hood, Brian L. ; Conrads, Thomas P. ; Leth-Larsen, Rikke ; Ditzel, Henrik J. / Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome. In: Cell Reports. 2019 ; Vol. 27, No. 13. pp. 3927-3938.e6.
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abstract = "Tumor eradication may be greatly improved by targeting cancer stem cells (CSCs), as they exhibit resistance to conventional therapy. To gain insight into the unique biology of CSCs, we developed patient-derived xenograft tumors (PDXs) from ER− breast cancers from which we isolated mammospheres that are enriched for CSCs. Comparative global proteomic analysis was performed on patient tumor tissues and corresponding PDXs and mammospheres. Mammospheres exhibited increased expression of proteins associated with de novo cholesterol synthesis. The clinical relevance of increased cholesterol biosynthesis was verified in a large breast cancer cohort showing correlation with shorter relapse-free survival. RNAi and chemical inhibition of the cholesterol biosynthesis pathway reduced mammosphere formation, which could be rescued by a downstream metabolite. Our findings identify the cholesterol biosynthesis pathway as central for CSC propagation and a potential therapeutic target, as well as providing a mechanistic explanation for the therapeutic benefit of statins in breast cancer. Ehmsen et al. identify cholesterol biosynthesis as essential for breast cancer stem cell propagation. Increased expression of multiple cholesterol biosynthesis proteins is observed in mammospheres, and the expression levels of these proteins correlate with the outcome of basal-like breast cancer patients. Inhibition of the cholesterol biosynthesis pathway reduces mammosphere formation.",
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Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome. / Ehmsen, Sidse; Pedersen, Martin H.; Wang, Guisong; Terp, Mikkel G.; Arslanagic, Amina; Hood, Brian L.; Conrads, Thomas P.; Leth-Larsen, Rikke; Ditzel, Henrik J.

In: Cell Reports, Vol. 27, No. 13, 25.06.2019, p. 3927-3938.e6.

Research output: Contribution to journalJournal articleResearchpeer-review

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AU - Ehmsen, Sidse

AU - Pedersen, Martin H.

AU - Wang, Guisong

AU - Terp, Mikkel G.

AU - Arslanagic, Amina

AU - Hood, Brian L.

AU - Conrads, Thomas P.

AU - Leth-Larsen, Rikke

AU - Ditzel, Henrik J.

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