CDK11^p58inhibits ERα-positive breast cancer invasion by targeting integrin β3 via the repression of ERα signaling

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.

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® 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.

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 ERα-positive breast cancer cells, but not ERα-negative breast cancer cells, in a kinase-dependent manner. Gene expression assays demonstrated that integrin β3 mRNA was dramatically repressed by CDK11^p58, and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11^p58 through ERα repression. The expression of integrin β3 was highly related to ERα signaling; ERα overexpression stimulated integrin β3 expression, whereas siRNA-mediated knockdown of ERα attenuated integrin β3 expression.

These data indicate that CDK11^p58 is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11^p58 via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.