The rapamycin-regulated gene expression signature determines prognosis for breast cancer

  • Akcakanat A
  • Zhang L
  • Tsavachidis S
 et al. 
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BACKGROUND: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. RESULTS: Colony formation and sulforhodamine B (IC50 < 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In the Wang dataset, RMI predicted time to disease relapse (P = 0.009). CONCLUSION: Rapamycin-regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment

Author-supplied keywords

  • Animals
  • Antibiotics,Antineoplastic
  • Breast
  • Breast Neoplasms
  • Cell Line,Tumor
  • Cell Proliferation
  • Cells
  • Clinical Trials
  • Disease
  • Dose-Response Relationship,Drug
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation,Neoplastic
  • Genes
  • Humans
  • In Vitro
  • Mammary Neoplasms,Experimental
  • Mice
  • Mice,Nude
  • Multivariate Analysis
  • Prognosis
  • Proportional Hazards Models
  • Research
  • Sirolimus
  • Survival Analysis
  • Time Factors
  • Tumor Stem Cell Assay
  • Xenograft Model Antitumor Assays
  • analysis
  • assay
  • breast cancer
  • cancer
  • clinical
  • drug
  • drug effects
  • drug therapy
  • gene expression
  • genetics
  • ic50
  • kinase
  • mTOR
  • pathology
  • pathway
  • pathways
  • pharmacology
  • rapamycin
  • statistics & numerical data
  • support
  • t
  • therapy

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  • PMID: 19778445


  • A Akcakanat

  • L Zhang

  • S Tsavachidis

  • F Meric-Bernstam

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