Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity

被引：156

作者：

Simoes, Bruno M. ^{[1
]}

O'Brien, Ciara S. ^{[1
]}

Eyre, Rachel ^{[1
]}

Silva, Andreia ^{[1
]}

Yu, Ling ^{[1
]}

Sarmiento-Castro, Aida ^{[1
]}

Alferez, Denis G. ^{[1
]}

Spence, Kath ^{[1
]}

Santiago-Gomez, Angelica ^{[1
]}

Chemi, Francesca ^{[1
,2
]}

Acar, Ahmet ^{[3
]}

Gandhi, Ashu ^{[4
]}

Howell, Anthony ^{[1
]}

Brennan, Keith ^{[3
]}

Ryden, Lisa ^{[5
]}

Catalano, Stefania ^{[2
]}

Ando, Sebastiano ^{[2
]}

Gee, Julia ^{[6
]}

Ucar, Ahmet ^{[1
,3
]}

Sims, Andrew H. ^{[7
]}

Marangoni, Elisabetta ^{[8
]}

Farnie, Gillian ^{[1
]}

Landberg, Goeran ^{[1
]}

Howell, Sacha J. ^{[1
]}

Clarke, Robert B. ^{[1
]}

机构：

[1] Univ Manchester, Inst Canc Sci, Breast Canc Now Res Unit, Manchester M20 4BX, Lancs, England

[2] Univ Calabria, Dept Pharm Hlth & Nutrit Sci, I-87036 Cosenza, Italy

[3] Univ Manchester, Fac Life Sci, Manchester M13 9PT, Lancs, England

[4] Univ S Manchester Hosp, NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Manchester M23 9LT, Lancs, England

[5] Lund Univ, Skane Univ Hosp, Clin Sci, Dept Surg, S-21428 Malmo, Sweden

[6] Cardiff Univ, Cardiff Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales

[7] Univ Edinburgh, Western Gen Hosp, Appl Bioinformat Canc Grp, Edinburgh EH4 2XU, Midlothian, Scotland

[8] Inst Curie, Lab Invest Preclin, F-75248 Paris 05, France

来源：

CELL REPORTS | 2015年 / 12卷 / 12期

基金：

英国医学研究理事会;

关键词：

ADJUVANT TAMOXIFEN; RECEPTOR; NOTCH; ESTROGEN;

D O I：

10.1016/j.celrep.2015.08.050

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.

引用

页码：1968 / 1977

页数：10

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