The
mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 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 S6K1/S6K2 gene amplification, as well as S6K2
protein expression in
breast cancer. S6K1/S6K2 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. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 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. S6K1 amplification was significantly associated with HER2 gene amplification and
protein expression. S6K2 amplification correlated significantly with high S6K2
mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 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 S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in
breast cancer.