The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling.
Overexpression of the receptor tyrosine kinase EPH receptor A2 (EphA2) is commonly observed in aggressive breast cancer and correlates with a poor prognosis. However, while EphA2 has been reported to enhance tumorigenesis, proliferation, and MAPK activation in several model systems, other studies suggest that EphA2 activation diminishes these processes and inhibits the activity of MAPK upon ligand stimulation. In this study, we eliminated EphA2 expression in 2 transgenic mouse models of mammary carcinoma. EphA2 deficiency impaired tumor initiation and metastatic progression in mice overexpressing ErbB2 (also known as Neu) in the mammary epithelium (MMTV-Neu mice), but not in mice overexpressing the polyomavirus middle T antigen in mammary epithelium (MMTV-PyV-mT mice). Histologic and ex vivo analyses of MMTV-Neu mouse mammary epithelium indicated that EphA2 enhanced tumor proliferation and motility. Biochemical analyses revealed that EphA2 formed a complex with ErbB2 in human and murine breast carcinoma cells, resulting in enhanced activation of Ras-MAPK signaling and RhoA GTPase. Additionally, MMTV-Neu, but not MMTV-PyV-mT, tumors were sensitive to therapeutic inhibition of EphA2. These data suggest that EphA2 cooperates with ErbB2 to promote tumor progression in mice and may provide a novel therapeutic target for ErbB2-dependent tumors in humans. Moreover, EphA2 function in tumor progression appeared to depend on oncogene context, an important consideration for the application of therapies targeting EphA2.
Brantley-Sieders
Dana M
DM
Department of Medicine, Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
Zhuang
Guanglei
G
Hicks
Donna
D
Fang
Wei Bin
WB
Hwang
Yoonha
Y
Cates
Justin M M
JM
Coffman
Karen
K
Jackson
Dowdy
D
Bruckheimer
Elizabeth
E
Muraoka-Cook
Rebecca S
RS
Chen
Jin
J
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D042361:Mammary Glands, Human / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D036104:Receptor, EphA2 / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020742:rhoA GTP-Binding Protein
D000952:Antigens, Polyomavirus Transforming; D036104:Receptor, EphA2; D018719:Erb-b2 Receptor Tyrosine Kinases; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C526380:RhoA protein, mouse