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

• Main Authors: Tsavachidis Spiridon, Zhang Li, Akcakanat Argun, Meric-Bernstam Funda
• Format: Article
• Language: English
• Published: BMC 2009-09-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/8/1/75

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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 <it>in vitro </it>and <it>in vivo </it>gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment <it>in vitro </it>as well as <it>in vivo </it>(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 (<it>P </it>= 0.015). On multivariate analysis, RMI (<it>P </it>= 0.029), tumor size (<it>P </it>= 0.015) and lymph node status (<it>P </it>= 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (<it>P </it>= 0.41). In the Wang dataset, RMI predicted time to disease relapse (<it>P </it>= 0.009).</p> <p>Conclusion</p> <p>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.</p>