Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
Cell Rep
; 12(12): 1968-77, 2015 Sep 29.
Article
em En
| MEDLINE
| ID: mdl-26387946
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
/
Neoplasias da Mama
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Proteínas de Ligação ao Cálcio
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Regulação Neoplásica da Expressão Gênica
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Proteínas Proto-Oncogênicas
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Resistencia a Medicamentos Antineoplásicos
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Antineoplásicos Hormonais
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Peptídeos e Proteínas de Sinalização Intercelular
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Receptores Notch
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Proteínas de Membrana
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Reino Unido