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Open Access Research article

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

Yayun Chi13, Sheng Huang13, Lei Wang23, Ruoji Zhou23, Lisha Wang23, Xiuying Xiao23, Dali Li23, Ying Cai23, Xiaoyan Zhou23 and Jiong Wu13*

Author Affiliations

1 Breast Cancer Institute; Department of Breast Surgery, Fudan University Shanghai Cancer Center, Building 7, No. 270 Dong An Road, Shanghai 200032, China

2 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China

3 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China

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BMC Cancer 2014, 14:577  doi:10.1186/1471-2407-14-577

Published: 8 August 2014

Abstract

Background

CDK11p58, 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. CDK11p58 is also involved in the regulation of steroid receptors, such as androgen and estrogen receptors. We previously found that CDK11p58 was abnormally expressed in prostate cancer. However, its role in breast cancer remains unclear.

Methods

CDK11p58 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 CDK11p58 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

CDK11p58 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 CDK11p58 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 CDK11p58, and luciferase results confirmed that the integrin β3 promoter was inhibited by CDK11p58 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.

Conclusions

These data indicate that CDK11p58 is an anti-metastatic gene in ERα-positive breast cancer and that the regulation of integrin β3 by CDK11p58 via the repression of ERα signaling may constitute part of a signaling pathway underlying breast cancer invasion.

Keywords:
CDK11p58; Metastasis; Integrinβ3; ERα; Tissue array; TaqMan assay