Geldanamycin destabilizes HER2 tyrosine kinase and suppresses Wnt/beta-catenin signaling in HER2 overexpressing human breast cancer cells.
HER2 (also known as ErbB2) is a transmembrane tyrosine kinase whose surface overexpression is linked to tumorigenesis and poor prognosis in breast cancer patients. beta-catenin is a substrate of this kinase, and HER2-dependent phosphorylation of tyrosine 654 leads to dissociation of the E-cadherin-beta-catenin membrane complex and increased Wnt signaling. beta-catenin-mediated Wnt signaling promotes proliferation and invasion of breast cancer cells. In this study, we show that HER2 binds to beta-catenin and that geldanamycin (GA), a drug that destabilizes HER2 protein, causes rapid depletion of HER2, thereby disrupting its association with beta-catenin in SKBr3 human breast cancer cells. Interestingly, GA did not affect the stability of beta-catenin protein, but altered its subcellular localization, driving it out of the nucleus and increasing its association with E-cadherin. Importantly, the change in subcellular localization of beta-catenin was also associated with a significant decrease in proliferation and motility of GA-treated breast cancer cells. Moreover, GA treatment led to reduced expression of the Wnt signaling target and cell cycle-promoting gene cyclin D1, providing a potential mechanism for the reduced proliferation. In conclusion, GA treatment suppressed tumorigenicity in the human breast cancer cell line SKBr3, at least in part through destabilization of the HER2 oncoprotein and repression of the Wnt/beta-catenin signaling pathway. These findings provide evidence for the clinical importance of GA in treatment of HER2 overexpressing breast cancers.
Wang
Ke
K
Department of Surgical Oncology, First Hospital of Xi'an Jiaotong University, 1 Jiankang Road, Xi'an 710061, P.R. China.
Ma
Qingyong
Q
Ren
Yu
Y
He
Jianjun
J
Zhang
Yong
Y
Zhang
Yunfeng
Y
Chen
Wuke
W
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D015820:Cadherins; D047029:Lactams, Macrocyclic; D018719:Erb-b2 Receptor Tyrosine Kinases; D051153:Wnt Proteins; D051176:beta Catenin; C001277:geldanamycin