TY - JOUR
T1 - Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
AU - M Simoes, Bruno
AU - O'Brien, Ciara
AU - Eyre, Rachel
AU - Silva, Andreia
AU - Yu, Ling
AU - Sarmiento Castro, Aida
AU - Alferez-Castro, Dennis
AU - Spence, Katherine
AU - Santiago-Gomez, Angelica
AU - Chemi, Francesca
AU - Acar, Ahmet
AU - Gandhi, Ashu
AU - Howell, Anthony
AU - Brennan, Keith
AU - Rydén, Lisa
AU - Catalano, Stefania
AU - Andó, Sebastiano
AU - Gee, Julia
AU - Ucar, Ahmet
AU - Sims, Andrew H.
AU - Marangoni, Elisabetta
AU - Farnie, Gillian
AU - Landberg, Goran
AU - Howell, Sacha
AU - Clarke, Robert B.
PY - 2015/9/29
Y1 - 2015/9/29
N2 - 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.
AB - 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.
U2 - 10.1016/j.celrep.2015.08.050
DO - 10.1016/j.celrep.2015.08.050
M3 - Article
C2 - 26387946
VL - 12
SP - 1968
EP - 1977
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -
