title: Neuregulin autocrine signaling promotes self-renewal of breast tumor-initiating cells by triggering HER2/HER3 activation.
abstract: Currently, only patients with HER2-positive tumors are candidates for HER2-targeted therapies. However, recent clinical observations suggest that the survival of patients with HER2-low breast cancers, who lack HER2 amplification, may benefit from adjuvant therapy that targets HER2. In this study, we explored a mechanism through which these benefits may be obtained. Prompted by the hypothesis that HER2/HER3 signaling in breast tumor-initiating cells (TIC) promotes self-renewal and survival, we obtained evidence that neuregulin 1 (NRG1) produced by TICs promotes their proliferation and self-renewal in HER2-low tumors, including in triple-negative breast tumors. Pharmacologic inhibition of EGFR, HER2, or both receptors reduced breast TIC survival and self-renewal in vitro and in vivo and increased TIC sensitivity to ionizing radiation. Through a tissue microarray analysis, we found that NRG1 expression and associated HER2 activation occurred in a subset of HER2-low breast cancers. Our results offer an explanation for why HER2 inhibition blocks the growth of HER2-low breast tumors. Moreover, they argue that dual inhibition of EGFR and HER2 may offer a useful therapeutic strategy to target TICs in these tumors. In generating a mechanistic rationale to apply HER2-targeting therapies in patients with HER2-low tumors, this work shows why these therapies could benefit a considerably larger number of patients with breast cancer than they currently reach.
authors.affiliation: Authors' Affiliations: Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine and Departments of Pathology and Radiation Oncology, Stanford University School of Medicine, Stanford, California; and Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Cleo Yi-Fang
authors.initials: CY
authors.lastname: Lee
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lin
authors.forename: Scott V
authors.initials: SV
authors.lastname: Bratman
authors.forename: Weiguo
authors.initials: W
authors.lastname: Feng
authors.forename: Angera H
authors.initials: AH
authors.lastname: Kuo
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Scheeren
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Engreitz
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
authors.forename: Maximilian
authors.initials: M
authors.lastname: Diehn
mesh_terms: D000818:Animals; D019898:Autocrine Communication / Q000235:genetics*; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D064593:Heterografts; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3