SIK2 functions as a novel tumor suppressor in the breast tumorigenesis

Abstract

Breast cancer has highly malignant phenotype and is the leading cause of cancer death in women. The heterogenous character of the disease points to the importance of novel target identification for the development of effective therapies. Perturbation in receptor tyrosine kinase (RTK) pathway elements are frequently implicated in cancer. Our group has shown that SIK2 functions downstream of FGFR signaling, and control proliferation and survival. Given the importance of strict control of RTK pathways in cancer, in this study, we aimed to investigate the potential role of SIK2 in the development of tumorigenicity. In this context, screening of a cDNA array indicated downregulation of SIK2 transcript levels in breast cancer. A query into Oncomine database validated frequent reduction of SIK2 expression and loss of copy number in dataset covering a large breast cancer patient cohort. Immunohistochemical studies localized SIK2 in ductal epithelia of breast tissue and showed that SIK2 levels decline in all triple negative breast cancer (TNBC) cases and in half of the hormone positive tumors. These studies also indicated that inverse correlation exists between SIK2 and Ki67 indicating a negative effect of SIK2 on mitotic potential. Reduced SIK2 expression in breast tumor cell lines was also evident. Modulation of SIK2 expression in MDA-MB-231 and MCF12A breast lines suggested that SIK2 negatively regulate proliferation and survival by preventing ERK and Akt activation. In this context, its kinase activity appears to be required. In vitro studies also indicate that SIK2 may also be involved in the regulation of cellular adhesion and invasion. Xenografting experiments provided strong evidence that SIK2 hampers tumor growth through downregulation of 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.