Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity
- PMID: 26387946
- PMCID: PMC4594158
- DOI: 10.1016/j.celrep.2015.08.050
Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity
Abstract
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.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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References
-
- Cottu P., Marangoni E., Assayag F., de Cremoux P., Vincent-Salomon A., Guyader Ch., de Plater L., Elbaz C., Karboul N., Fontaine J.J. Modeling of response to endocrine therapy in a panel of human luminal breast cancer xenografts. Breast Cancer Res. Treat. 2012;133:595–606. - PubMed
-
- Creighton C.J., Li X., Landis M., Dixon J.M., Neumeister V.M., Sjolund A., Rimm D.L., Wong H., Rodriguez A., Herschkowitz J.I. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl. Acad. Sci. USA. 2009;106:13820–13825. - PMC - PubMed
-
- Davies C., Godwin J., Gray R., Clarke M., Cutter D., Darby S., McGale P., Pan H.C., Taylor C., Wang Y.C., Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378:771–784. - PMC - PubMed
-
- Farnie G., Clarke R.B., Spence K., Pinnock N., Brennan K., Anderson N.G., Bundred N.J. Novel cell culture technique for primary ductal carcinoma in situ: role of Notch and epidermal growth factor receptor signaling pathways. J. Natl. Cancer Inst. 2007;99:616–627. - PubMed
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