Nuclear ErbB-2: a Novel Therapeutic Target in ErbB-2-Positive Breast Cancer?

Abstract

Membrane overexpression of ErbB-2 (MErbB-2), a member of the ErbB family of receptor tyrosine kinases, occurs in 15-20% of breast cancers (BC) and constitutes a therapeutic target in this BC subtype (ErbB-2-positive). Although MErbB-2-targeted therapies have significantly improved patients' clinical outcome, resistance to available drugs is still a major issue in the clinic. Lack of accurate biomarkers for predicting responses to anti-ErbB-2 drugs at the time of diagnosis is also an important unresolved issue. Hence, a better understanding of the ErbB-2 signaling pathway constitutes a critical task in the battle against BC. In its canonical mechanism of action, MErbB-2 activates downstream signaling pathways, which transduce its proliferative effects in BC. The dogma of ErbB-2 mechanism of action has been challenged by the demonstration that MErbB-2 migrates to the nucleus, where it acts as a transcriptional regulator. Accumulating findings demonstrate that nuclear ErbB-2 (NErbB-2) is involved in BC growth and metastasis. Emerging evidence also reveal a role of NErbB-2 in the response to available anti-MErbB-2 agents. Here, we will review NErbB-2 function in BC and will particularly discuss the role of NErbB-2 as a novel target for therapy in ErbB-2-positive BC.

Keywords: Breast cancer; ErbB-2 signaling pathway; Metastasis; Nuclear ErbB-2; Response to ErbB-2-targeted therapies; Transcriptional coactivator.

Fig. 1

Canonical and non-canonical actions of ErbB-2 in breast cancer (BC). a ErbB-2 canonical signaling pathway. Upon ligand binding, ErbBs form homodimers or heterodimers, which activate downstream signaling cascades and transduce ErbBs effects. Heregulin-induced ErbB-2/ErbB-3 heterodimers are illustrated. The two key signaling pathways activated are p42/p44 mitogen-activated protein kinases (MAPKs) and phosphatidylinositol 3-kinase (PI3K)/AKT. Activation of the MAPK pathway leads to the transcription of genes that drive cellular proliferation, migration, and angiogenesis, while activation of the PI3K/AKT pathway leads to downstream cellular endpoints including cell survival and apoptosis suppression (reviewed in [17]). Altogether, activation of these signaling cascades promotes BC growth and metastasis. b ErbB-2 non-canonical action. ErbB-2 non-canonical action involves nuclear translocation of membrane ErbB-2. Heregulin-induced ErbB-2/ErbB-3 heterodimerization and nuclear translocation is depicted [19]. Once in the nucleus, ErbB-2 may directly bind to its response elements and function as a transcription factor (TF), or may tether to other TFs and act as a transcriptional coactivator. An example of ErbB-2 acting as a transcriptional coactivator is shown. NErbB-2 actions also drive BC growth and metastasis