Activation of the Akt/mammalian target of rapamycin/4E-BP1 pathway by ErbB2 overexpression predicts tumor progression in breast cancers.
The Akt/mammalian target of rapamycin (mTOR)/4E-BP1 pathway is considered to be a central regulator of protein synthesis, involving the regulation of cell proliferation, differentiation, and survival. The inhibitors of mTOR as anticancer reagents are undergoing active evaluation in various malignancies including breast cancer. However, the activation status of the Akt/mTOR/4E-BP1 pathway and its potential roles in breast cancers remain unknown. Thus, we examined 165 invasive breast cancers with specific antibodies for the phosphorylation of Akt, mTOR, and 4E-BP1 by immunohistochemistry and compared them with normal breast epithelium, fibroadenoma, intraductal hyperplasia, and ductal carcinoma in situ. We discovered that the phosphorylation of Akt, mTOR, and 4E-BP1 increased progressively from normal breast epithelium to hyperplasia and abnormal hyperplasia to tumor invasion. Phosphorylated Akt, mTOR, and 4E-BP1 were positively associated with ErbB2 overexpression. Survival analysis showed that phosphorylation of each of these three markers was associated with poor disease-free survival independently. In vitro, we further confirmed the causal relationship between ErbB2 overexpression and mTOR activation, which was associated with enhanced invasive ability and sensitivity to a mTOR inhibitor, rapamycin. Our results, for the first time, demonstrate the following: (a) high levels of phosphorylation of Akt, mTOR, and 4E-BP1 in breast cancers, indicating activation of the Akt/mTOR/4E-BP1 pathway in breast cancer development and progression; (b) a link between ErbB2 and the Akt/mTOR/4E-BP1 pathway in breast cancers in vitro and in vivo, indicating the possible role of Akt/mTOR activation in ErbB2-mediated breast cancer progression; and (c) a potential role for this pathway in predicting the prognosis of patients with breast cancer, especially those treated with mTOR inhibitors.
Zhou
Xiaoyan
X
Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Tan
Ming
M
Stone Hawthorne
Valerie
V
Klos
Kristine S
KS
Lan
Keng-Hsueh
KH
Yang
Ying
Y
Yang
Wentao
W
Smith
Terry L
TL
Shi
Daren
D
Yu
Dihua
D
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D018734:Genes, erbB-2; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011494:Protein Kinases / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus / Q000494:pharmacology; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011494:Protein Kinases; C546842:MTOR protein, human; D011505:Protein-Tyrosine Kinases; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus