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

Simões, Bruno M; O'Brien, Ciara S; Eyre, Rachel; Silva, Andreia; Yu, Ling; Sarmiento-Castro, Aida; Alférez, Denis G; Spence, Kath; Santiago-Gómez, Angélica and Chemi, Francesca, et al. (2015) In Cell Reports 12(12). p.1968-1977
Abstract
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... (More)
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. (Less)
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Cell Reports
volume
12
issue
12
pages
1968 - 1977
publisher
Cell Press
external identifiers
  • pmid:26387946
  • wos:000362022600003
  • scopus:84942838396
ISSN
2211-1247
DOI
10.1016/j.celrep.2015.08.050
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English
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yes
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05936050-0c04-4b32-a629-aefb5d8e759c (old id 8035804)
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http://www.ncbi.nlm.nih.gov/pubmed/26387946?dopt=Abstract
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2015-10-03 18:36:08
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@article{05936050-0c04-4b32-a629-aefb5d8e759c,
  abstract     = {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.},
  author       = {Simões, Bruno M and O'Brien, Ciara S and Eyre, Rachel and Silva, Andreia and Yu, Ling and Sarmiento-Castro, Aida and Alférez, Denis G and Spence, Kath and Santiago-Gómez, Angélica and Chemi, Francesca and Acar, Ahmet and Gandhi, Ashu and Howell, Anthony and Brennan, Keith and Rydén, Lisa and Catalano, Stefania and Andó, Sebastiano and Gee, Julia and Ucar, Ahmet and Sims, Andrew H and Marangoni, Elisabetta and Farnie, Gillian and Landberg, Göran and Howell, Sacha J and Clarke, Robert B},
  issn         = {2211-1247},
  language     = {eng},
  number       = {12},
  pages        = {1968--1977},
  publisher    = {Cell Press},
  series       = {Cell Reports},
  title        = {Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.},
  url          = {http://dx.doi.org/10.1016/j.celrep.2015.08.050},
  volume       = {12},
  year         = {2015},
}