Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
Résumé
The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. () and () are situated in the commonly amplified 17q21-23 and 11q13 regions. amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of / gene amplification, as well as S6K2 protein expression in breast cancer. / gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. amplification/gain was detected in 10.7%/21.4% and amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. amplification was significantly associated with gene amplification and protein expression. amplification correlated significantly with high mRNA levels, ER+ status and amplification. and gene amplification was associated with a worse prognosis independent of and . gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR− subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that amplification and overexpression, like amplification, have prognostic and treatment predictive significance in breast cancer.
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