Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms

• Published in: Oncogene Vol. 28; no. 10; pp. 1309 - 1319
• Main Authors: Hollmén, M, Määttä, J A, Bald, L, Sliwkowski, M X, Elenius, K
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.03.2009; Nature Publishing Group
• Subjects: Animals; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Apoptosis; Biological and medical sciences; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Care and treatment; Cell Biology; Cell growth; Cell physiology; Cell proliferation; Cell Proliferation - drug effects; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Child, Preschool; ErbB-2 protein; Female; Fundamental and applied biological sciences. Psychology; Genetics; Gynecology. Andrology. Obstetrics; Health aspects; Histology; Human Genetics; Humans; Internal Medicine; Isoforms; Male; Mammary gland diseases; Medical sciences; Medicine; Medicine & Public Health; Mice; Mice, Inbred BALB C; Molecular and cellular biology; Monoclonal antibodies; Oncogenes; Oncology; original-article; Phosphorylation; Physiological aspects; Protein Isoforms; Proteolysis; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Receptor, Epidermal Growth Factor - chemistry; Receptor, Epidermal Growth Factor - metabolism; Receptor, ErbB-4; Statistical analysis; Trastuzumab; Tumor cell lines; Tumorigenesis; Tumors; Tyrosine; Ubiquitination; Finland; ectodomain shedding; therapeutic antibodies; neuregulins; EGFR; HER4; Molecular form; Breast disease; Targeting; Growth; Suppression; Breast cancer; Malignant tumor; Monoclonal antibody; Carcinogenesis; Mammary gland diseases; Neuregulin; Cancer
• DOI: 10.1038/onc.2008.481
• ISSN: 0950-9232

ErbB4 isoforms mediate different cellular activities depending on their susceptibility to proteolytic cleavage. The biological significance of ErbB4 cleavage in tumorigenesis, however, remains poorly understood. Here, we describe characterization of a monoclonal antibody (mAb 1479) that selectively recognizes the ectodomain of cleavable ErbB4 JM-a isoforms both in vitro and in vivo . mAb 1479 was used to analyse ErbB4 JM-a expression and ectodomain shedding in a series of 17 matched breast cancer/histologically normal peripheral breast tissue pairs. ErbB4 ectodomain was observed in 75% of tumors expressing ErbB4 but only in 18% of normal breast tissue samples expressing ErbB4. Difference in the relative quantity of ErbB4 ectodomain between normal and tumor tissue pairs was statistically significant ( P =0.015). Treatment with mAb 1479 suppressed ErbB4 function by inhibiting ErbB4 tyrosine phosphorylation and ectodomain shedding, and by stimulating ErbB4 downregulation and ubiquitination. mAb 1479 suppressed both anchorage-dependent and -independent growth of human breast cancer cell lines that naturally express cleavable ErbB4 JM-a. These findings indicate that ErbB4 ectodomain shedding is enhanced in breast cancer tissue in vivo , and that mAb 1479 represents a potential drug candidate that suppresses breast cancer cell growth by selectively binding cleavable ErbB4 isoforms.