SIK2 attenuates proliferation and survival of breast cancer cells with simultaneous perturbation of MAPK and PI3K/Akt pathways

// Neslihan Zohrap 1 , Ozge Saatci 2 , Burcak Ozes 1 , Ipek Coban 3 , Hasan Murat Atay 4 , Esra Battaloglu 1 , Ozgur Şahin 2 and Kuyas Bugra 1, 5 1 Department of Molecular Biology and Genetics, Bogazici University, Istanbul, Turkey 2 Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey 3 Department of Pathology, Istanbul Florence-Nightingale Hospital, Istanbul, Turkey 4 Department of General Surgery, Gayrettepe Florence-Nightingale Hospital, Istanbul, Turkey 5 Life Sciences Center, Bogazici University, Istanbul, Turkey Correspondence to: Kuyas Bugra, email: bugra@boun.edu.tr Keywords: SIK2; tumor suppressor; breast cancer; Ras/ERK and PI3K/Akt signaling; EMT Received: October 19, 2017      Accepted: March 09, 2018      Published: April 24, 2018 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.