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

Research output: Contribution to journalJournal articleResearchpeer-review

164 Downloads (Pure)

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

Keywords

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

Fingerprint Dive into the research topics of 'Increased Cholesterol Biosynthesis Is a Key Characteristic of Breast Cancer Stem Cells Influencing Patient Outcome'. Together they form a unique fingerprint.

Cite this