Revealing potentially different roles of the mTOR-targets S6K1 and S6K2 in breast cancer by expression profiling and structural analysis
2014 (English)Manuscript (preprint) (Other academic)
Background The AKT/mTORC1/S6K pathway is frequently overstimulated in breast cancer, consequently constituting a promising therapeutic target. The benefit from mTOR inhibitors varies, likely as a consequence of tumour heterogeneity, and upregulation of several compensatory feed-back mechanisms. The mTORC1 downstream effectors S6K1, S6K2, and 4EBP1 are amplified and overexpressed in breast cancer, associated with a poor outcome and divergent endocrine treatment benefit. S6K1 and S6K2 share high sequence homology, but evidence of partly distinct biological functions are emerging.
Aim Explore possible different roles and treatment target potentials of S6K1 and S6K2 in breast cancer.
Materials and methods Whole-genome expression profiling was performed on breast tumours expressing high levels of S6K1, S6K2 or 4EBP1, using public datasets, as well as after in vitro siRNA downregulation of S6K1 and/or S6K2 in ZR751 breast cancer cells. In silico homology modelling of the S6K2 kinase domain was used to evaluate its possible structural divergences to S6K1.
Results and discussion S6K1 and S6K2 positive profiles of breast cancers were highly different, whereas S6K2 and 4EBP1 profiles showed significant overlaps, both correlated to genes involved in cell cycle progression, among these the master regulator E2F1. S6K2 and 4EBP1 were inversely associated with IGF1 levels, and their prognostic value was shown to be restricted to tumours positive for IGFR and/or HER2. In vitro, S6K1 and S6K2 silencing resulted in upregulation of genes in the mTORC1 and mTORC2 complexes. Isoform-specific silencing also showed distinct patterns, e.g. S6K2 downregulation leads to upregulation of several cell cycle associated genes. Structural analyses of the S6K2 kinase domain showed unique structure patterns, deviating from these of S6K1, facilitating the development of isoform-specific inhibitors.
Conclusion Our data support emerging proposals of distinct biological features of S6K1 and S6K2, suggesting their importance as separate oncogenes and clinical markers, where specific targeting in different breast cancer subtypes could facilitate further individualised therapies.
Place, publisher, year, edition, pages
Cancer and Oncology
IdentifiersURN: urn:nbn:se:liu:diva-104179OAI: oai:DiVA.org:liu-104179DiVA: diva2:695097