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

Cell Rep. 2019 Jun 25;27(13):3927-3938.e6. doi: 10.1016/j.celrep.2019.05.104.

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.

Keywords: PDX tumors; breast cancer stem cells; cholesterol biosynthesis pathway; mammospheres; proteome profiling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cholesterol / biosynthesis*
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Mice
  • Mice, Inbred NOD
  • Mice, Transgenic
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Triple Negative Breast Neoplasms / drug therapy
  • Triple Negative Breast Neoplasms / metabolism*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Cholesterol