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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
  • Bruno M Simões
  • Ciara S O'Brien
  • Rachel Eyre
  • Andreia Silva
  • Ling Yu
  • Aida Sarmiento-Castro
  • Denis G Alférez
  • Kath Spence
  • Angélica Santiago-Gómez
  • Francesca Chemi
  • Ahmet Acar
  • Ashu Gandhi
  • Anthony Howell
  • Keith Brennan
  • Stefania Catalano
  • Sebastiano Andó
  • Julia Gee
  • Ahmet Ucar
  • Andrew H Sims
  • Elisabetta Marangoni
  • Gillian Farnie
  • Göran Landberg
  • Sacha J Howell
  • Robert B Clarke
Enheter & grupper
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
Originalspråkengelska
Sidor (från-till)1968-1977
TidskriftCell Reports
Volym12
Utgivningsnummer12
StatusPublished - 2015
PublikationskategoriForskning
Peer review utfördJa

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