The role of S6K1 in ER-positive breast cancer

Abstract

T he 40S ribosomal S6 kinase 1 (S6K1) is a conserved serine/threonine protein kinase that belongs to the AGC family of protein kinases, which also includes Akt and many others. S6K1 is the principal kinase effector downstream of the mammalian target of rapamycin complex 1 (mTORC1). S6K1 is sensitive to a wide range of signaling inputs, including growth factors, amino acids, energy levels and hypoxia. S6K1 relays these signals to regulate a growing list of substrates and interacting proteins in control of oncogenic processes, such as cell growth and proliferation, cell survival and apoptosis and cell migration and invasion. Several lines of evidence suggest an important role for S6K1 in estrogen receptor (ER)-positive breast cancer. S6K1 directly phosphorylates and activates ERα. Furthermore, S6K1 expression is estrogenically regulated. Therefore, hyperactivation of mTORC1/ S6K1 signaling may be closely related to ER-positive status in breast cancer and may be utilized as a marker for prognosis and a therapeutic target. IntroductionThe mTORC1 signaling pathway. Since its cloning and biochemical purification almost 20 y ago, mTOR, a conserved protein kinase, emerged as a central node in the plexus coordinating cellular growth and proliferation in response to numerous extracellular cues, including nutrient availability and growth stimuli. In eukaryotic cells, mTOR exists in two complexes. mTORC1 and mTORC2 consist of distinct sets of proteins and perform non-redundant functions. 1 a naturally derived inhibitor of mTORC1 and an inhibitor of cell proliferation, as manifested by its potent immunosuppressive properties and activity against solid tumors. 2 Growth factor signaling to mTORC1 is primarily mediated by the phosphatidylinositol-3 kinase (PI3K) pathway and inactivation of the tuberous sclerosis complex protein TSC2 (tuberin). As illustrated in Figure 1, in response to extracellular activating stimuli, PI3K mediates cell membrane recruitment and activation of the serine/threonine protein kinases phosphatidylinositol-dependent kinase-1 (PDK1) and Akt. 3,4 The lipid phosphatase PTEN opposes the action of PI3K. TSC2 functions as a heterodimer with TSC1 (hamartin) to negatively regulate mTORC1 signaling by acting as a GTPase-activating protein (GAP) for the small GTPase Rheb. 5 Rheb directly binds to mTORC1 and regulates its activity in a GTP-dependent manner. 6 Thus, TSC2 inhibits Rheb-dependent activation of mTORC1. Phosphorylation and inactivation of TSC2 has first been shown to occur via PI3K/Akt. 7 Subsequently, several groups have shown that the Ras/ERK pathway also converges on the TSC1/2 complex. Ras-activated ERK1/2 directly phosphorylates TSC2 at sites different than Akt, resulting in TSC2 inactivation. 8 The downstream effector of ERK, RSK, also phosphorylates TSC2 at a unique site, thus inactivating it. 9 Therefore, TSC2 serves as a convergence point for multiple signaling inputs to mTORC1.Activation of S6K1. S6K1 is one of the best-characterized downstream targets of mTORC1, and rapamycin treatment re...

ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer

“…This was not evident for nuclear ERRα, although trends were in the same direction. In the ER-positive group we found a close association between cytoplasmic ERRα and the 40S ribosomal S6 kinase 1 (S6K1), the best-characterized kinase downstream of the mechanistic target of rapamycin (mTOR) (28, 29), which we recently found to reduce proliferation and response to tamoxifen (30), but the association was not evident when ERRα was localized to the nucleus (Supplementary Table S1). Nuclear ERRα was frequently overexpressed in tumors with an active AKT/mTOR-pathway, a signature we found to predict tamoxifen benefit (25).…”

From bench to bedside: What do we know about hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer?

“…AKT phosphorylates PRAS40 and also activates mTORC1 via tuberous sclerosis 1/2 (TSC1/2). mTORC1 mediates cell metabolism, cell size and protein translation and synthesis via its two major downstream substrates, 40S ribosomal protein S6 kinase 1 (S6K1) and eukaryotic inhibition factor 4E binding protein (4EBP1) [80]. mTORC2 contains mTORC, mLST8, Rictor and DEPTOR.…”

P-mTOR Expression and Implication in Breast Carcinoma: A Systematic Review and Meta-Analysis

“…mTOR consists of two independent functional complexes, mTORC1 and mTORC2, which can be phosphorylated to p-mTOR. mTORCs directly phosphorylate and activate ribosome S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1) [8, 9]. Their effect on activating 4EBP1 inhibits their capacity to repress the mRNA cap-binding protein eukaryotic initiation factor 4E (eIF4E) [10, 11].…”