Carboxyl-terminal modulator protein positively regulates Akt phosphorylation and acts as an oncogenic driver in breast cancer.
Akt activation has been implicated broadly in tumorigenesis, but the basis for its dysregulation in cancer cells is incompletely understood. In this study, we sought to clarify a regulatory role for the Akt-binding carboxy-terminal modulator protein (CTMP), which has been controversial. In evaluating CTMP expression in paired normal-tumor specimens of 198 patients with breast cancer, we found that CTMP was upregulated in breast tumors, where it was associated with poor patient survival. Notably, CTMP expression also correlated positively with Akt phosphorylation in breast cancer clinical specimens and cell lines. Furthermore, ectopic expression of CTMP promoted cell proliferation and enhanced the tumorigenic properties of estrogen-dependent breast cancer cells. This effect was correlated with increased sensitivity to insulin-induced Akt phosphorylation, which is mediated primarily by the phosphoinositide 3-kinase-Akt pathway. In contrast, short hairpin RNA-mediated silencing of endogenous CTMP decreased the proliferation of estrogen-dependent or estrogen-independent breast cancer cells. Mechanistic investigations defined the N-terminal domain of CTMP at amino acids 1 to 64 as responsible for Akt binding. Taken together, our results firmly corroborate the concept that CTMP promotes Akt phosphorylation and functions as an oncogenic molecule in breast cancer.
Authors' Affiliations: Institute of Clinical Medicine, National Cheng Kung University, Tainan; Department of Medical Education and Research, Kaohsiung Veterans General Hospital; Departments of Surgery and Emergency Medicine, Kaohsiung Veterans General Hospital, Kaohsiung; Genomics Research Center, Academia Sinica; and Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Yu-Peng
YP
Liu
Wen-Chi
WC
Liao
Luo-Ping
LP
Ger
Jiun-Chin
JC
Chen
Tai-I
TI
Hsu
Yu-Cheng
YC
Lee
Hong-Tai
HT
Chang
Yu-Chia
YC
Chen
Yi-Hua
YH
Jan
Kuen-Haur
KH
Lee
Yu-Hao
YH
Zeng
Michael
M
Hsiao
Pei-Jung
PJ
Lu
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013869:Thiolester Hydrolases / Q000378:metabolism*; D046888:Tissue Array Analysis; D014162:Transfection
D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C076744:cytoplasmic linker protein 170; D051057:Proto-Oncogene Proteins c-akt; C437985:THEM4 protein, human; D013869:Thiolester Hydrolases