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 (TICs) 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 breast cancer patients than they currently reach.

Heregulin/ErbB3 Signaling Enhances CXCR4-Driven Rac1 Activation and Breast Cancer Cell Motility via Hypoxia-Inducible Factor 1α

“…Increasing evidence links HRG/ErbB3 signaling to mammary tumorigenesis and metastasis. In addition, studies have assigned key roles to autocrine HRG-mediated activation of ErbB3/ErbB2 in sustaining tumor growth and conferring resistance to therapeutic agents (15,17,25,26,28,(72)(73)(74). The fact that ErbB3 signals primarily through activation of the PI3K pathway (1,7,8) invariably argues for a prominent role of the receptor in shifting the balance toward enhanced cell survival, invasiveness, and the maintenance of the tumor phenotype.…”

“…SDF-1 activates the Rac1 small GTPase to promote breast cancer cell motility (40). Since elevated production of the ErbB ligand HRG occurs in a significant proportion of breast tumors (5,6,15,17), we decided to examine the effect of persistent HRG treatment on CXCR4-mediated Rac1 activation and motility in breast cancer cells. To this end, breast cancer cells (BT-474, MDA-MB-361, and MCF-7) were subjected to prolonged treatment with HRG (10 ng/ml; 16 h).…”

“…ErbB3 expression in invasive human breast carcinomas has been associated with reduced patient survival (13). Enhanced production of HRG, which could be induced by oncogenic inputs, such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) mutations, occurs in a significant proportion of breast tumors, including ErbB2-low tumors (6,(14)(15)(16)(17). Notably, transgenic overexpression of HRG in mouse mammary glands leads to the development of adenocarcinomas (18).…”

Intratumoral Heterogeneity: From Diversity Comes Resistance

“…Trials are currently under way to assess whether the endocrine therapy index of CTCs is correlated with patient outcome (28). Heterogeneous expression of the ERBB3 (HER3) and its ligand NRG1 have been reported in a variety of human cancers, including breast cancer, lung cancer, and glioblastoma (23,29,30). HER3 signals as heterodimer with other receptors of the HER family leading to potent activation of the PI3K/AKT pathway (22).…”

“…Although HER2 targeted therapies are currently only approved to treat patients with HER2-positive disease, analysis of results from two adjuvant trastuzumab (anti-HER2) trials revealed that patients with Her2-low tumors also benefit from adjuvant treatment (35,36). On the basis of these findings, Lee and colleagues explored the role of HER2 signaling in CSCs from Her2-low tumors and found that activation of HER2/HER3 by NRG1 autocrine signaling supports their proliferation and self-renewal (30). NRG1 alone is sufficient to support mammosphere formation by breast CSCs (37), and NRG1 also stimulates the growth of primary lung CSCs in sphere cultures (38).…”