Abstract
BackgroundMammalian 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.ResultsColony 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).ConclusionRapamycin-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.
Highlights
Mammalian target of rapamycin 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
PTEN is downregulated in one third of patients with breast cancer [8] and PTEN loss is associated with poor prognosis for this malignancy [9]
Identification of differentially expressed genes in breast cancer cells and generation of a rapamycin-regulated gene expression signature We sought to identify genes differentially expressed in response to treatment with rapamycin in MDA-MB-468 cells, a PTEN-null human breast cancer cell line with constitutive activation of phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling [23,24,25]
Summary
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. MTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. We tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth [1]. The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway in particular is deregulated in many cancers, including breast cancer. PI3K activates Akt, which regulates various cellular processes and promotes cell survival. MTOR is a downstream effector of the PI3K/Akt pathway and phosphorylates S6 kinase (S6K1) and 4E-binding protein-1. Various aberrations activate mTOR, which has a key role in translation, cell growth, apoptosis and angiogenesis
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