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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 publication




Journal article


Cell reports

Publication Date





1968 - 1977


Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.


Cell Line, Tumor, Animals, Humans, Mice, Breast Neoplasms, p-Aminoazobenzene, Tamoxifen, Benzazepines, Estradiol, Isoenzymes, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Cell Cycle Proteins, Homeodomain Proteins, Membrane Proteins, Proto-Oncogene Proteins, Receptors, Estrogen, Antineoplastic Agents, Hormonal, Survival Analysis, Xenograft Model Antitumor Assays, Signal Transduction, Cell Proliferation, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Female, Retinal Dehydrogenase, Basic Helix-Loop-Helix Transcription Factors, Receptors, Notch, Neoplastic Stem Cells, Estrogen Receptor Antagonists, Transcription Factor HES-1, Jagged-1 Protein, Serrate-Jagged Proteins