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

Date

2015-09-01

Author

Simoes, Bruno M.
O'Brien, Ciara S.
Eyre, Rachel
Silva, Andreia
Yu, Ling
Sarmiento-Castro, Aida
Alferez, Denis G.
Spence, Kath
Santiago-Gomez, Angelica
Chemi, Francesca
Acar, Ahmet
Gandhi, Ashu
Howell, Anthony
Brennan, Keith
Ryden, Lisa
Catalano, Stefania
Ando, Sebastiano
Gee, Julia
Ucar, Ahmet
Sims, Andrew H.
Marangoni, Elisabetta
Farnie, Gillian
Landberg, Goeran
Howell, Sacha J.
Clarke, Robert B.

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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.

URI

https://hdl.handle.net/11511/89499

Journal

CELL REPORTS

DOI

https://doi.org/10.1016/j.celrep.2015.08.050

Collections

Department of Biology, Article

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Citation Formats

B. M. Simoes et al., “Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity,” CELL REPORTS, pp. 1968–1977, 2015, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/89499.