SIK2 functions as a novel tumor suppressor in the breast tumorigenesis

Breast cancer with high malignancy is the leading cause of cancer death in women. The heterogeneity emphasizes the importance of novel target identification for the efficient therapies. Perturbations in receptor tyrosine kinase (RTK) pathway elements are frequently implicated in cancer. Our group indicated that SIK2 functions downstream of FGFR signaling, and control proliferation and survival. Given the importance of strict control of RTK pathways in cancer, this study aims to investigate SIK2 potential role in the tumorigenicity. In this context, screening of a cDNA array indicated depleted SIK2 levels in breast cancer. Oncomine database screen validated frequent reduction of SIK2 expression and copy number loss in a large sample set. Immunohistochemical studies has shown SIK2 expression in ductal epithelia of breast tissue and level decline in all triple negative breast cancer cases and in some hormone positive tumors. The studies indicated that inverse correlation exists between SIK2 and Ki67 indicating a negative effect of SIK2 on mitotic potential. Reduced SIK2 in breast tumor cell lines is evident. Modulation of SIK2 expression in MDA-MB-231 and MCF12A lines suggested that SIK2 negatively regulate proliferation and survival by preventing ERK and Akt activation. In this context, its kinase activity is required. In vitro studies highlighted that SIK2 may also be involved in cellular adhesion and invasion regulation. Xenografting experiments provided strong evidence that SIK2 hampers tumor growth via downregulating proliferation and survival. In the light of these findings, we propose SIK2 as a novel tumor suppressor, loss of its expression/activity promote breast tumorigenesis.