HER2 splice variants and their relevance in breast cancer

The HER2 gene amplification occurs in 20-30% of breast cancer and is correlated with a poorer prognosis compared to HER2-negative disease due to increased proliferation and metastatic potential. Two major types of receptor inhibitors have been developed for therapy and one for each categories is currently used in clinic: i) the humanized monoclonal antibody trastuzumab, directed against the HER2 extracellular domain; and ii) the EGFR/HER2 dual tyrosine kinase inhibitor lapatinib. However, patients may develop resistance to drugs and show disease progression. Several mechanism of resistance have been explored and are still under investigation. Here, we focus our attention on the role played by the alternative splicing forms of HER2 in mediating HER2 oncogenic activity and in conditioning the response to HER2 therapies. Three HER2 splice variants have been described so far; the p100 and the herstatin give raise to two secreted proteins of 100 kd and 68 kd, respectively, that act as cell growth inhibitors. The third splice form of HER2 gene is the Δ16HER2, encoding for a receptor lacking exon16, whose absence determines constitutive active dimers with transforming activity in vitro and in vivo. The Δ16HER2 binds to trastuzumab to a less extend, due to conformational changes of the extracellular domain and its levels are supposed to increase proportionally to the increasing of the HER2 wild-type copy numbers in human primary breast cancers. Finally, HER2 carboxy-terminal fragments (CTFs), generated by alternative initiation of translation, were observed in breast cancer patients. In particular, 611-CTF, activating multiple signaling pathways since it is expressed as a constitutively active homodimer, was suggested to be a potent oncogene capable of promoting mammary tumour progression and metastasis. Despite the evidences of a potential role of the naturally occurring inhibitors p100 and herstatin on the wild-type HER2 and its signaling pathway, to date they do not seem to have a possible clinical development. To date the most promising forms currently under investigation that could have a key role in determining the increased HER2-positive tumours aggressiveness and toward the development of bio-drugs are the HER2Δ16 and the CTFs.