The HER2 Signaling Network in Breast Cancer—Like a Spider in its Web

Abstract

The human epidermal growth factor receptor 2 (HER2) is a major player in the survival and proliferation of tumour cells and is overexpressed in up to 30 % of breast cancer cases. A considerable amount of work has been undertaken to unravel the activity and function of HER2 to try and develop effective therapies that impede its action in HER2 positive breast tumours. Research has focused on exploring the HER2 activated phosphoinositide-3-kinase (PI3K)/AKT and rat sarcoma/mitogen-activated protein kinase (RAS/MAPK) pathways for therapies. Despite the advances, cases of drug resistance and recurrence of disease still remain a challenge to overcome. An important aspect for drug resistance is the complexity of the HER2 signaling network. This includes the crosstalk between HER2 and hormone receptors; its function as a transcription factor; the regulation of HER2 by protein-tyrosine phosphatases and a complex network of positive and negative feedback-loops. This review summarises the current knowledge of many different HER2 interactions to illustrate the complexity of the HER2 network from the transcription of HER2 to the effect of its downstream targets. Exploring the novel avenues of the HER2 signaling could yield a better understanding of treatment resistance and give rise to developing new and more effective therapies.

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

“…The phosphorylated tyrosines then act as docking sites for proteins which activate various signaling cascades including the RAS/RAF/MEK and PI3K/AKT pathways. 5 Although HER2 has no known ligand it maintains a continuously active conformation and can form heterodimers with other members of the EGF family, or homodimers when expressed at high concentrations. HER2 is the preferred binding partner of all the other ErbB receptors, 6,7 and also appears to amplify the signaling of the other receptors resulting in heterodimers with potent mitogenic activity.…”

ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

“…It is worth noting that further ampliication of the ErbB2 signaling may derive from its crosstalk with other signaling mediators. For instance, it has been demonstrated that ErbB2 can cross-talk with hormone receptors, insulin growth factor receptor (IGFR), protein phosphatases, transforming growth beta receptor (TGFR-beta) and ion channels resulting in a complex signaling network that contribute to tumor growth and progression [15].…”

“…Several downstream signaling pathways are activated after ErbB2 receptor activation leading to the regulation of cell proliferation, growth and survival as well as invasion and angiogenesis [15]. Tyrosine residues phosphorylation resulting from receptor activation can recruit a variety of intracellular adaptor and scafold proteins that in turn mediate the activation of downstream signaling pathways.…”

“…The activation of RAS promotes a cascade of downstream kinase activation that ultimately leads to the phosphorylation and activation of extracellular signal-regulated kinases 1 and 2 (ERK1, ERK2) [17,18]. Activated ERK proteins phosphorylate a number of transcription factors such as Elk-1, c-Fos and c-Jun among others, that regulate the expression of genes implicated in cell growth, diferentiation, proliferation, survival and migration [15,19].…”

Gab2 Ablation Reverses the Stemness of HER2-Overexpressing Breast Cancer Cells

“…Between 15% and 23% of breast cancers show amplification and/or overexpression of the human epidermal growth factor receptor-2 (HER2) gene [3-5]. This receptor is mainly involved in signaling pathways that regulate cell proliferation, differentiation, migration, and apoptosis [6-9]. HER2 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinases.…”