HER2 splice variants in breast cancer: investigating their impact on diagnosis and treatment outcomes.

Vic Hart,Alison Tyson-Capper,John Kirby,Hannah Gautrey

doi:10.18632/oncotarget.27789

Abstract

Overexpression of the HER2 receptor occurs in approximately 20% of breast cancer patients. HER2 positivity is associated with poor prognosis and aggressive tumour phenotypes, which led to rapid progress in HER2 targeted therapeutics and diagnostic testing. Whilst these advances have greatly increased patients’ chances of survival, resistance to HER2 targeted therapies, be that intrinsic or acquired, remains a problem.Different forms of the HER2 protein exist within tumours in tandem and can display altered biological activities. Interest in HER2 variants in breast cancer increased when links between resistance to anti-HER2 therapies and a particular variant, Δ16-HER2, were identified. Moreover, the P100 variant potentially reduces the efficacy of the anti-HER2 therapy trastuzumab. Another variant, Herstatin, exhibits ‘auto-inhibitory’ behaviour. More recently, new HER2 variants have been identified and are currently being assessed for their pro- and anti-cancer properties.It is important when directing the care of patients to consider HER2 variants collectively. This review considers HER2 variants in the context of the tumour environment where multiple variants are co-expressed at altered ratios. This study also provides an up to date account of the landscape of HER2 variants and links this to patterns of resistance against HER2 therapies and treatment plans.

Highlights

Human epidermal growth factor receptorBreast cancer occurs in 1 in 8 women within their lifetime and is the second highest cause of cancer related deaths in the UK [1, 2]
This review considers HER2 variants in the context of the tumour environment where multiple variants are co-expressed at altered ratios
Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer is a subgroup defined by overexpression of the HER2 tyrosine kinase receptor, which transduces biochemical signals across the cell membrane and amplification of the HER2 gene, ErBb2 [3]

Summary

Introduction

Human epidermal growth factor receptorBreast cancer occurs in 1 in 8 women within their lifetime and is the second highest cause of cancer related deaths in the UK [1, 2]. Human Epidermal Growth Factor Receptor 2 positive (HER2+) breast cancer is a subgroup defined by overexpression of the HER2 tyrosine kinase receptor, which transduces biochemical signals across the cell membrane and amplification of the HER2 gene, ErBb2 [3]. As the dimerization is asymmetrical the kinase domain from one receptor allosterically activates the other via this phosphorylation [8] These C-terminal tyrosine residues act as docking sites, providing the location for the subsequent activation of downstream signalling molecules. Shedding of the www.oncotarget.com extracellular domain (ECD) can occur through cleavage performed by matrix metalloproteases, leaving only the intracellular domain (ICD) [10, 11] This can mediate signalling by altering dimer formation [12, 13]

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Conclusion