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: Cleo Yi-Fang Lee, Yuan Lin, Scott V Bratman, Weiguo Feng, Angera H Kuo, Ferenc A Scheeren, Jesse M Engreitz, Sushama Varma, Robert B West, Maximilian Diehn
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 1 Pg. 341-52 (Jan 01 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24177178 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Neuregulin-1
• Receptor, ErbB-2
• Receptor, ErbB-3

Topics

• Animals
• Autocrine Communication (genetics)
• Breast Neoplasms (enzymology, genetics, metabolism, pathology)
• Cell Line, Tumor
• Female
• Heterografts
• Humans
• Mammary Neoplasms, Experimental (enzymology, genetics, metabolism, pathology)
• Mice
• Neoplastic Stem Cells (enzymology, metabolism, pathology)
• Neuregulin-1 (genetics, metabolism)
• Receptor, ErbB-2 (genetics, metabolism)
• Receptor, ErbB-3 (genetics, metabolism)
• Signal Transduction