ErbB-2 induces bilateral adrenal pheochromocytoma formation in mice.
Pheochromocytoma (PCC) is a rare catecholamine-producing tumor that arises from the adrenal medulla and is often familial. The genetic basis for familial PCC involves mutations of RET, VHL, SHDx or NF-1 in more than 20% of cases. Additional genes may be important in pathogenesis of both familial and sporadic PCC. ErbB-2/Her2/Neu is a growth factor receptor tyrosine kinase that is frequently overexpressed in tumors and there is clinical evidence suggesting that enhanced ErbB-2 growth factor receptor signaling may play a role in PCC. In the present study, ectopic expression of an activated ErbB-2 transgene resulted in bilateral adrenal PCC. Analyses of tumor samples and normal adrenal tissue revealed that levels of the Pten tumor suppressor protein were greatly reduced in PCCs, while levels of the cell cycle regulatory protein cyclin D1 were usually increased. In addition, levels of phospo-AKT were increased in PCCs versus normal adrenal tissue. Biochemical analyses established that PCC's were functionally active, producing abundant levels of the catecholamines, epinephrine and norepinephrine. These data establish that increased ErbB-2 growth factor receptor signaling in the adrenal medulla can lead to PCC through combined influences on Pten, AKT andcyclin D1.
Lombardi Cancer Comprehensive Center, Department of Oncology, Georgetown University Medical Center, Washington, DC 20057, USA.
Edwin W
EW
Lai
Olga C
OC
Rodriguez
Maral
M
Aventian
Caroline
C
Cromelin
Stanley T
ST
Fricke
Lucia
L
Martiniova
Irina A
IA
Lubensky
Michael P
MP
Lisanti
Kristen L
KL
Picard
James F
JF
Powers
Arthur S
AS
Tischler
Karel
K
Pacak
Chris
C
Albanese
D000310:Adrenal Gland Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019938:Cyclin D1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D007150:Immunohistochemistry; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000235:genetics; D010673:Pheochromocytoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
D019938:Cyclin D1; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases