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

Cell Rep. 2015 Sep 29;12(12):1968-77. doi: 10.1016/j.celrep.2015.08.050. Epub 2015 Sep 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1
  • Animals
  • Antineoplastic Agents, Hormonal / pharmacology*
  • Basic Helix-Loop-Helix Transcription Factors / antagonists & inhibitors
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Benzazepines / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism*
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Estrogen Receptor Antagonists / pharmacology
  • Female
  • Fulvestrant
  • Gene Expression Regulation, Neoplastic*
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Jagged-1 Protein
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / pathology
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Receptor, Notch4
  • Receptors, Estrogen / genetics
  • Receptors, Estrogen / metabolism
  • Receptors, Notch / antagonists & inhibitors
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism*
  • Retinal Dehydrogenase / antagonists & inhibitors
  • Retinal Dehydrogenase / genetics
  • Retinal Dehydrogenase / metabolism
  • Serrate-Jagged Proteins
  • Signal Transduction
  • Survival Analysis
  • Tamoxifen / pharmacology
  • Transcription Factor HES-1
  • Xenograft Model Antitumor Assays
  • p-Aminoazobenzene / analogs & derivatives
  • p-Aminoazobenzene / pharmacology

Substances

  • 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide
  • Aldehyde Dehydrogenase 1
  • Antineoplastic Agents, Hormonal
  • Basic Helix-Loop-Helix Transcription Factors
  • Benzazepines
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • Estrogen Receptor Antagonists
  • HEY1 protein, human
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Isoenzymes
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Estrogen
  • Receptors, Notch
  • Serrate-Jagged Proteins
  • Transcription Factor HES-1
  • Tamoxifen
  • HES1 protein, human
  • Fulvestrant
  • C.I. Solvent Yellow 56
  • Estradiol
  • p-Aminoazobenzene
  • ALDH1A1 protein, human
  • Aldh1 protein, mouse
  • Retinal Dehydrogenase