Activation of the mTOR signaling pathway in breast cancer and its correlation with the clinicopathologic variables
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Rapamycin and its analogues are currently being tested in clinical trials as novel–targeted anticancer agents. Pre-clinical studies that used breast cancer cell lines have suggested that p-Akt or p-S6K1 expressing tumors, as well as PTEN negative tumors, were sensitive to rapamycin. The aims of this study were to determine the proportion of breast cancer that could be candidates for rapamycin treatment and to elucidate the clinicopathologic characteristics and prognosis of potentially rapamycin-sensitive tumors.
We evaluated the expressions of PTEN, p-Akt and p-S6K1 by performing immunohistochemistry in 122 breast cancer tissues. We analyzed the association of the expression of these proteins with the cliniopathologic variables and the disease-free survival.
PTEN negative tumors, p-Akt expressing tumors and p-S6K1 expressing tumors constituted 4.1% (5/122), 41.0% (50/122), and 36.1% (44/122) of the total tumors, respectively. The proportion of tumors that met the criteria of rapamycin sensitivity was 54.9% (67/122). We could not find any significant correlation between the expression of these proteins and the other prognostic factors. However, the prognosis of tumors with a p-S6K1 expression was significantly worse than that of the p-S6K1 negative tumors.
Based on the status of the PTEN, p-Akt and p-S6K1 expressions as predictors of rapamycin sensitivity, this study suggested that over 50% of breast cancer patients could be potential candidates for rapamycin treatment. In addition, the p-S6K1 expression may constitute an independent prognostic factor for disease-free survival.
KeywordsBreast cancer mTOR Phosphorylated Akt Phosphorylated S6 kinase Prognostic factor PTEN Rapamycin
- 3.Noh WC, Paik NS (2003) Translational regulation: a novel target for breast cancer therapy. J Korean Breast Cancer Soc 6:8–14Google Scholar
- 8.O’Donnell M, Faivre I, Judson C et al (2003) A phase I study of oral mTOR inhibitor RAD 001 as monotherapy to identify the optimal biologically effective dose using toxicity, pharmacokinetic and pharmacodynamic endpoints in patients with solid tumors. Proc Am Soc Clin Oncol 22:200Google Scholar
- 12.Chow LWC, Sun Y, Jassem J et al (2006) Phase 3 study of temsirolimus with letrozole or letrozole alone in postmenopausal women with locally advanced or metastatic breast cancer. Paper presented at the 29th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 2006Google Scholar
- 18.Nelen MR, van Staveren WC, Peeters E et al (1997) Germline mutation in the PTEN/MMAC-1 gene in patients with Cowden disease. Human Mol Genet 6:1384–1387Google Scholar