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
Affiliations
Sidse Ehmsen
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark; Department of Oncology, Odense University Hospital, 5000 Odense, Denmark; Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark
Martin H. Pedersen
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark
Guisong Wang
Women’s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Annandale, VA 22003, USA
Mikkel G. Terp
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark
Amina Arslanagic
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark
Brian L. Hood
Women’s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Annandale, VA 22003, USA
Thomas P. Conrads
Women’s Health Integrated Research Center at Inova Health System, Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences and Walter Reed National Military Medical Center, Annandale, VA 22003, USA; Inova Schar Cancer Institute, Inova Center for Personalized Health, Fairfax, VA 22031, USA
Rikke Leth-Larsen
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark; Department of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark; Corresponding author
Henrik J. Ditzel
Department of Molecular Medicine, Cancer, and Inflammation Research Unit, University of Southern Denmark, 5000 Odense, Denmark; Department of Oncology, Odense University Hospital, 5000 Odense, Denmark; Department of Clinical Research, University of Southern Denmark, 5000 Odense, Denmark; Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, 5000 Odense, Denmark; Corresponding author
Summary: 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. Keywords: cholesterol biosynthesis pathway, breast cancer stem cells, PDX tumors, proteome profiling, mammospheres
