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

作者：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

来源：Cell Reports, 2015, 12(12): 1968-1977.

DOI：10.1016/j.celrep.2015.08.050

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.

• 出版日期2015-9-29