Targeting the Akt/mTOR pathway in Brca1-deficient cancers.
The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1-deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers.
Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO 63108, USA.
T
T
Xiang
Y
Y
Jia
D
D
Sherris
S
S
Li
H
H
Wang
D
D
Lu
Q
Q
Yang
D000818:Animals; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D001578:Benzopyrans / Q000494:pharmacology; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D019313:BRCA1 Protein; D001578:Benzopyrans; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C533469:palomid 529
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