Proteolytic Processing of ErbB4 in Breast Cancer

Abstract

ErbB4 is a receptor tyrosine kinase that can signal by a mechanism involving proteolytic release of intracellular and extracellular receptor fragments. Proteolysis-dependent signaling of ErbB4 has been proposed to be enhanced in breast cancer, mainly based on immunohistochemical localization of intracellular epitopes in the nuclei. To more directly address the processing of ErbB4 in vivo, an ELISA was developed to quantify cleaved ErbB4 ectodomain from serum samples. Analysis of 238 breast cancer patients demonstrated elevated quantities of ErbB4 ectodomain in the serum (≥40 ng/mL) in 21% of the patients, as compared to 0% of 30 healthy controls (P = 0.002). Significantly, the elevated serum ectodomain concentration did not correlate with the presence of nuclear ErbB4 immunoreactivity in matched breast cancer tissue samples. However, elevated serum ectodomain concentration was associated with the premenopausal status at diagnosis (P = 0.04), and estradiol enhanced ErbB4 cleavage in vitro. A 3.4 Å X-ray crystal structure of a complex of ErbB4 ectodomain and the Fab fragment of anti-ErbB4 mAb 1479 localized the binding site of mAb 1479 on ErbB4 to a region on subdomain IV encompassing the residues necessary for ErbB4 cleavage. mAb 1479 also significantly blocked ErbB4 cleavage in breast cancer cell xenografts in vivo, and the inhibition of cleavage was associated with suppression of xenograft growth. These data indicate that ErbB4 processing is enhanced in breast cancer tissue in vivo, and that ErbB4 cleavage can be stimulated by estradiol and targeted with mAb 1479.

Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer

“…Four different HER4 mRNA spliced isoforms known as JM-a/CYT1, JM-a/CYT2, JM-b/CYT1 and JM-b/CYT2 have been reported, which are derived from the alternative HER4 mRNA splicing [30, 50, 51]. In contrast to JM-b variant, the JM-a region consists of Adam-17 (TACE) cleavage site that allows initial process of HER4 proteolytic cleavage to produce the extracellular domain (ECD) and intracellular domain (ICD) [25, 29, 52].…”

Comprehensive Profiling of EGFR/HER Receptors for Personalized Treatment of Gynecologic Cancers

“…Proteolysis results in generation of an intracellular domain fragment that has functions distinct from that of the intact receptor. Nuclear HER4 has been detected in several cancer types, including medulloblastoma and breast cancer, and shed HER4 ectodomain has been detected in serum from breast cancer patients [14]. In preclinical models, inhibition of HER4 proteolysis with a blocking antibody represses xenograft tumor growth in mice [14].…”

“…Nuclear HER4 has been detected in several cancer types, including medulloblastoma and breast cancer, and shed HER4 ectodomain has been detected in serum from breast cancer patients [14]. In preclinical models, inhibition of HER4 proteolysis with a blocking antibody represses xenograft tumor growth in mice [14]. However, the importance of HER4 intracellular/ectodomain fragments as prognostic markers and drivers of disease remain poorly defined.…”

rs11895168 C allele and the increased risk of breast cancer in Isfahan population

“…Despite of the controversial aspect of association between ErbB4 expression signature and clinical outcomes including the survival of breast cancer patients [5e9, 33], mice xenograft along with in vitro studies have proposed an oncogenic role for ErbB4 protein in breast cancer [10,34,35]. A number of population-based GWAS studies have demonstrated that germ-line ErbB4 variations are associated with breast cancer risk, including rs13393577, rs905883, rs7564590, rs7558615.…”