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

Bruno M Simoes, Ciara O'Brien, Rachel Eyre, Andreia Silva, Ling Yu, Aida Sarmiento Castro, Dennis Alferez-Castro, Katherine Spence, Angelica Santiago-Gomez, Francesca Chemi, Ahmet Acar, Ashu Gandhi, Anthony Howell, Keith Brennan, Lisa Rydén, Stefania Catalano, Sebastiano Andó, Julia Gee, Ahmet Ucar, Andrew H. SimsElisabetta Marangoni, Gillian Farnie, Goran Landberg, Sacha Howell, Robert B. Clarke

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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.
Original languageEnglish
Pages (from-to)1968-1977
Number of pages9
JournalCell Reports
Issue number12
Publication statusPublished - 29 Sept 2015


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