Abstract
Salt Inducible Kinase2 (SIK2) has been shown to contribute to tumorigenesis in multiple tumor types in a dichotomous manner. However, little is known about its contribution to breast malignancies. Here, we report SIK2 as a potential tumor suppressor in breast cancer whose expression was reduced in tumor tissues and breast cancer cell lines compared to normal counterparts. In vitro loss- and gain-of-function experiments combined with xenograft studies demonstrated that SIK2-mediated attenuation of proliferation and survival of breast cancer cells with parallel inhibition of both Ras/Erk and PI3K/Akt pathways. Our findings elucidated that SIK2 has also an inhibitory role in migration/invasion ability of breast cancer cells through regulation of epithelial mesenchymal transition. Immunostaining of patient tumors revealed that SIK2 protein level is frequently downregulated in invasive mammary carcinomas and negatively correlated with the mitotic activity of the cells in triple negative breast cancers and hormone positive tumors. Strikingly, patient survival analysis indicated that higher levels of SIK2 are significantly associated with better survival, especially in basal breast cancer cases. Overall, our findings suggest SIK2 as a potential tumor suppressor in the control of breast tumorigenesis, at least in part, via inhibiting PI3K/Akt and Ras/ERK signaling cascades simultaneously and a novel prognostic marker, especially in basal subtypes of breast cancer.
Highlights
Breast cancer is the second leading cause of cancer related deaths among women worldwide
Ras/ERK and PI3K/Protein Kinase-B (Akt) pathways are triggered by diverse ligands and frequently hyper-activated in human breast cancers
We report that Salt Inducible Kinase2 (SIK2) is implicated in simultaneous inhibition of Ras/ERK and PI3K/Akt signaling pathways to attenuate proliferation, survival and motility of the breast cells
Summary
Breast cancer is the second leading cause of cancer related deaths among women worldwide It is a complex disease with inter-/ intra-tumor molecular heterogeneity which affects disease progression and treatment responses [1,2]. Breast cancer classification based on molecular profiling approaches have contributed to a better understanding of breast cancer biology and led to five major subtypes: luminal A/B, basal-like, HER2(+), normal breastlike [3,4]. This allowed for the development of targeted therapies for some specific subtypes, e.g. tamoxifen for luminal-A tumors and trastuzumab for HER2+ subtype. Finding novel targets and biomarkers is needed for better management of the disease, especially for basal breast cancers for which no efficient therapy options available
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