HER2-PI9 and HER2-I12: two novel and functionally active splice variants of the oncogene HER2 in breast cancer.

In this study, two novel alternative splice variants of HER2, named HER2-PI9 and HER2-I12, were identified in breast cancer cell lines and breast tumour tissues. Whilst HER2-P19 arises from the inclusion of an 117 bp cassette-exon of intron 9 of HER2, HER2-I12 results from intron 12 inclusion. In silico analyses were performed to predict the amino acid sequences of these two HER2 novel variants. To confirm their protein expression, plasmid vectors were generated and transfected into the HER2 negative breast cancer cell line, MCF-7. Additionally, their functional properties in oncogenic signalling were confirmed. Expression of HER2-PI9 and HER2-I12 was successful and matched the in silico predictions. Importantly, these splice variants can modulate the phosphorylation levels of extracellular signal-related kinase 1/2 (ERK1/2) and Akt/protein kinase B (Akt) signalling in MCF-7 breast cancer cells. Enhanced cellular proliferation, migration and invasion were observed in the case of the HER2-I12 expressing model. In human tissues and breast carcinoma tumours both variants were present. This study reveals two novel splice variants of HER2. Additionally, the potential biological activity for HER2-PI9 and HER2-I12 in breast cancer cells is also reported..

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

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.