Suppression of breast cancer cell growth by a monoclonal antibody targeting cleavable ErbB4 isoforms.
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.
Hollmén
M
M
Medicity Research Laboratories, Department of Medical Biochemistry and Genetics, University of Turku, Turku, Finland.
Määttä
J A
JA
Bald
L
L
Sliwkowski
M X
MX
Elenius
K
K
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002675:Child, Preschool; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D020033:Protein Isoforms; D066247:Receptor, ErbB-4; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020033:Protein Isoforms; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4; D000068878:Trastuzumab