CDK11p58 inhibits ERα-positive breast cancer invasion by targeting integrin β3 via the repression of ERα signaling

Background: CDK11(p58), a Ser/Thr kinase that belongs to the cell division cycle 2-like 1 (CDC2L1) subfamily, is associated with cell cycle progression, tumorigenesis and apoptotic signaling. CDK11(p58) is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11(p58) was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear. Methods: CDK11(p58) expression was evaluated by immunohistochemical staining in a tissue array. A Transwell assay was used to detect invasion and metastasis in breast cancer cells. The TaqMan (R) Metastasis Gene Expression Assay was used to search for potential downstream factors in the CDK11(p58) signaling pathway. qRT-PCR was used to evaluate mRNA levels, and the dual luciferase array was used to analyze promoter activity. Western blotting was used to detect the protein level. Results: CDK11(p58) expression was negatively correlated with node status (P = 0.012), relapse status (P = 0.002) and metastasis status (P = 0.023). Kaplan-Meier survival curves indicated that the disease-free survival (DFS) was significantly poor in breast cancer patients with low CDK11 expression. Interestingly, using the breast cancer cell lines ZR-75-30 and MDA-MB-231, we found that CDK11(p58) was capable of repressing the migration and invasion of ER alpha-positive breast cancer cells, but not ER alpha-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin beta 3 mRNA was dramatically repressed by CDK11(p58), and luciferase results confirmed that the integrin beta 3 promoter was inhibited by CDK11(p58) through ER alpha repression. The expression of integrin beta 3 was highly related to ER alpha signaling; ER alpha overexpression stimulated integrin beta 3 expression, whereas siRNA-mediated knockdown of ER alpha attenuated integrin beta 3 expression. Conclusions: These data indicate that CDK11(p58) is an anti-metastatic gene in ER alpha-positive breast cancer and that the regulation of integrin beta 3 by CDK11(p58) via the repression of ER alpha signaling may constitute part of a signaling pathway underlying breast cancer invasion.