A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors.
The Akt pathway is commonly deregulated in many cancers. Clinical trials are currently underway to test the effectiveness of breast cancer treatment by inhibition of various Akt pathway intermediates. A set of genes induced by Akt in a transgenic mouse model, a subset of which were sensitive to mammalian target of rapamycin (mTOR) inhibitor RAD001, was examined in five public gene expression profile data sets of clinical breast tumor specimens (representing >1000 different samples in all). In each of the clinical data sets, the Akt mouse model genes as a group were significantly overexpressed in human tumors having high levels of AKT1 mRNA. The subset of genes both upregulated by Akt and dependent on mTOR activity were associated with estrogen receptor-negative status, higher grade, increasing tumor size and poor prognosis in multiple patient cohorts; these associations were either not present or not as strong for the Akt-induced, mTOR-independent genes or for AKT1 expression alone. The genes shown here to be relevant to Akt-mTOR both experimentally and pathologically have the potential for use in a molecular diagnostic to determine which patients should receive mTOR antagonist treatment.
Creighton
C J
CJ
Department of Medicine, Dan L Duncan Cancer Center, Division of Biostatistics, Baylor College of Medicine, Houston, TX 77030, USA. creighto@bcm.tmc.edu
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011379:Prognosis; D011494:Protein Kinases / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D012333:RNA, Messenger; D011494:Protein Kinases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases