CD36-Mediated Metabolic Rewiring of Breast Cancer Cells Promotes Resistance to HER2-Targeted Therapies

被引：149

作者：

Feng, William W. ^{[1
,11
]}

Wilkins, Owen ^{[2
]}

Bang, Scott ^{[11
]}

Ung, Matthew ^{[1
]}

Li, Jiaqi ^{[1
]}

An, Jennifer ^{[6
]}

del Genio, Carmen ^{[6
]}

Canfield, Kaleigh ^{[1
]}

DiRenzo, James ^{[1
]}

Wells, Wendy ^{[7
,8
]}

Gaur, Arti ^{[6
]}

Robey, R. Brooks ^{[3
,5
,9
]}

Guo, Jessie Yanxiang ^{[12
]}

Powles, Ryan L. ^{[13
]}

Sotiriou, Christos ^{[14
]}

Pusztai, Lajos ^{[13
]}

Febbraio, Maria ^{[10
]}

Cheng, Chao ^{[1
,4
,8
,15
]}

Kinlaw, William B. ^{[3
,8
]}

Kurokawa, Manabu ^{[1
,11
]}

机构：

[1] Geisel Sch Med Dartmouth, Dept Mol & Syst Biol, Hanover, NH 03755 USA

[2] Geisel Sch Med Dartmouth, Dept Epidemiol, Hanover, NH 03755 USA

[3] Geisel Sch Med Dartmouth, Dept Med, Hanover, NH 03755 USA

[4] Geisel Sch Med Dartmouth, Dept Biomed Data Sci, Hanover, NH 03755 USA

[5] Geisel Sch Med Dartmouth, Dept Med Educ, Hanover, NH 03755 USA

[6] Dartmouth Hitchcock Med Ctr, Dept Neurol, Lebanon, NH 03756 USA

[7] Dartmouth Hitchcock Med Ctr, Dept Pathol, Lebanon, NH 03756 USA

[8] Norris Cotton Canc Ctr, Lebanon, NH 03756 USA

[9] White River Junct Vet Affairs Med Ctr, White River Jct, VT 05009 USA

[10] Univ Alberta, Dept Dent, Edmonton, AB, Canada

[11] Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA

[12] Rutgers Canc Inst New Jersey, New Brunswick, NJ 08903 USA

[13] Yale Sch Med, Yale Canc Ctr, Breast Med Oncol, New Haven, CT 05620 USA

[14] Univ Libre Bruxelles, Inst Jules Bordet, Breast Canc Translat Res Lab JC Heuson, Brussels, Belgium

[15] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

来源：

CELL REPORTS | 2019年 / 29卷 / 11期

基金：

美国国家卫生研究院;

关键词：

FATTY-ACID SYNTHASE; UP-REGULATION; SURVIVAL; GROWTH; TRASTUZUMAB; PROLIFERATION; METASTASIS; INHIBITORS; OXIDATION; LAPATINIB;

D O I：

10.1016/j.celrep.2019.11.008

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Although it is established that fatty acid (FA) synthesis supports anabolic growth in cancer, the role of exogenous FA uptake remains elusive. Here we show that, during acquisition of resistance to HER2 inhibition, metabolic rewiring of breast cancer cells favors reliance on exogenous FA uptake over de novo FA synthesis. Through cDNA microarray analysis, we identify the FA transporter CD36 as a critical gene upregulated in cells with acquired resistance to the HER2 inhibitor lapatinib. Accordingly, resistant cells exhibit increased exogenous FA uptake and metabolic plasticity. Genetic or pharmacological inhibition of CD36 suppresses the growth of lapatinib-resistant but not lapatinib-sensitive cells in vitro and in vivo. Deletion of Cd36 in mammary tissues of MMTVneu mice significantly attenuates tumorigenesis. In breast cancer patients, CD36 expression increases following anti-HER2 therapy, which correlates with a poor prognosis. Our results define CD36-mediated metabolic rewiring as an essential survival mechanism in HER2-positive breast cancer.

引用

页码：3405 / +

页数：21

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