Involvement of S6 Kinase in Breast Cancer

Sridharan, S., Involvement of S6 Kinase in Breast Cancer. Doctor of Philosophy (Cancer Biology), November 2013, 129pp, 19 illustrations, 215 references. The 40S ribosomal protein S6 Kinase (S6K) is activated downstream of the mammalian target of rapamycin (mTOR)and is believed to play and important role in protein translation. In mammalian cells S6K is represented by two highly homologous proteins, S6K1 and S6K2. Both homologs have been shown to be amplicfied and over expressed in breast cancer cells and tissues. While the regulation and functions of S6K1 have been addressed, little is known about those of S6K2 . Hence we sought to examine the causes and consequences of elevated S6K2 levels in breast cancer cells. While the depletion of S6K1 decreased breast cancer cell death, silencing of S6K2 substantially increased it in response to apoptotic and chemotherapeutic agents. We then explored the mechanism by which S6K2 mediates survival and observed that in contrast to S6K1, S6K2 depletion decreased the activation of the prosurvival protein Akt and increased the level of proapoptotic proteins p53 and bid. Following this observation, we sought to determine the pathways(s) contributing to the overexpression of S6K2 in breast cancer cells. Due to its role as a prognostic indicator in estrogen receptor (ER) – positive tumors, we studied the role of the estrogen signaling pathways in regulating S6K2 levels. Estradiol and estrogen receptor alpha (ERα) positively regulated S6K2 protein but did not affect its mRNA levels, suggesting post-transcriptional regulation. We further observed that S6K2 regulated cell survival downstream of estrogen in ER-positive breast cancer cells. These findings strongly suggest that S6K2 is critical for the survival of breast cancer cells and that targeting S6K2 in combination with chemotherapeutic agents is a novel strategy to promote breast cancer cell death.