HER2 splice variants and their relevance in breast cancer

Abstract

<p class="MsoNormal" style="background: white; margin: 0cm 0cm 0pt; text-align: justify;"><span style="font-size: small;"><span lang="EN-US">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.<span style="color: #231f20;"> 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<span style="mso-spacerun: yes;"> </span></span>tyrosine kinase inhibitor lapatinib. </span><span lang="EN-US">However, patients may develop resistance to</span><span lang="EN-US"> drugs and show</span><span lang="EN-US"> disease progression</span><span lang="EN-US">. Several resistant mechanisms have been explored and are still under investigation. Here, </span><span lang="EN-GB">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 gave raised to two secreted proteins of 100 kd and 68 kd, respectively that act as cell growth inhibitors. Herstatin has been described for its ability to interrupt the constitutive HER2 activation, but also for its capacity to hamper HER2 dimerization with the others HER receptors. Interestingly, herstatin, present as mRNA and protein in non cancerous tissue in areas adjacent to breast carcinoma, is absent as protein in 75% of mammary tumors, </span><span lang="EN-US">which indicates that cancer cells are protected by some intrinsic mechanism against the putative growth-inhibitory effects of this naturally occurring molecule. The third splice form of HER2 gene is the Δ16HER2, encoding for a receptor lacking exon16, whose absence determines a 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.<span style="mso-spacerun: yes;"> </span>The Δ16HER2 accounts for almost 9% of the total HER2 transcripts in human breast cancers and, additionally, Δ16HER2 levels are supposed to increase proportionally at the increasing of the HER2 wild-type copy numbers in human primary breast cancers. The availability of a specific assay to determine and quantify the expression levels of this splicing form and the availability of Δ16HER2 transgenic mice models made this variant as the most promising for the development of biodrugs. </span></span></p><span style="font-size: 12pt;" lang="EN-US">Finally, HER2 carboxy-terminal fragments (CTFs), generated by alternative initiation of translation, were observed in breast cancer patients. In particular, 611-CTF was described to activate multiple signaling pathways since it is expressed as a constitutively active homodimer. Express...

Clinical Significance of HER-2 Splice Variants in Breast Cancer Progression and Drug Resistance

“…Cancer-specific events can result in proteins with “procancer” properties which may promote malignant transformation or confer a survival advantage on cancer cells, such as resistance to treatment [27–29]. In recent years, focus has been directed at the level of the transcriptome with one area of continued investigation centred on the different variants of HER-2 that can be produced by alternative splicing [30–33]. …”

“…As new therapeutic strategies are devised in efforts to tackle current problems with treatment resistance, attention has been directed to further unravel the impact of HER-2 with particular focus on these spliced variants [30]. Studies have investigated the transforming, oncogenic and drug-resistant activities of these isoforms [30, 33–35]. …”

“…Studied in cell lines and tumours derived from breast cancer and gastric cancer, p100 has the capacity to inhibit tumour cell proliferation [34, 38]. Further exploration reported a decrease in downstream signal induction such as the MAP kinase pathways [30]. …”

“…Several studies have provided evidence that this secreted truncated form of HER-2 may serve as a serum biomarker particularly in informing treatment decisions [30, 39, 40]. Leyland-Jones et al demonstrated reduced levels of p100 expression in more aggressive tumours [39].…”

“…Leyland-Jones et al demonstrated reduced levels of p100 expression in more aggressive tumours [39]. Further studies in breast cancer have continued to evaluate its role as a biomarker, and its value remains an issue for debate [30, 41]. Some reports suggest that this variant may compete for selection by monoclonal antibodies such as trastuzumab thereby interfering with its treatment activity [38, 41].…”