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

被引：142

作者：

Ehmsen, Sidse ^{[1
,6
,7
]}

Pedersen, Martin H. ^{[1
]}

Wang, Guisong ^{[2
,3
]}

Terp, Mikkel G. ^{[1
]}

Arslanagic, Amina ^{[1
]}

Hood, Brian L. ^{[2
,3
]}

Conrads, Thomas P. ^{[2
,3
,4
]}

Leth-Larsen, Rikke ^{[1
,5
]}

Ditzel, Henrik J. ^{[1
,6
,7
]}

机构：

[1] Univ Southern Denmark, Canc & Inflammat Res Unit, Dept Mol Med, DK-5000 Odense, Denmark

[2] Uniformed Serv Univ Hlth Sci, Womens Hlth Integrated Res Ctr, Inova Hlth Syst, Gynecol Canc Ctr Excellence,Dept Obstet & Gynecol, Annandale, VA 22003 USA

[3] Walter Reed Natl Mil Med Ctr, Annandale, VA 22003 USA

[4] Inova Ctr Personalized Hlth, Inova Schar Canc Inst, Fairfax, VA 22031 USA

[5] Univ Southern Denmark, Dept Reg Hlth Res, DK-5000 Odense, Denmark

[6] Odense Univ Hosp, Dept Oncol, DK-5000 Odense, Denmark

[7] Univ Southern Denmark, Acad Geriatr Canc Res AgeCare, DK-5000 Odense, Denmark

来源：

CELL REPORTS | 2019年 / 27卷 / 13期

关键词：

TUMOR XENOGRAFTS; STATIN USE; RISK; MOUSE; IDENTIFICATION; RECURRENCE; EVOLUTION; REVEALS; MODEL;

D O I：

10.1016/j.celrep.2019.05.104

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：3927 / +

页数：18

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