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Low molecular weight cyclin E is specific in breast cancer and is associated with mechanisms of tumor progression

Hannah Wingate, Agnes Puskas, Mylinh Duong, Tuyen Bui, Dana Richardson, Yanna Liu, Susan L. Tucker, Carolyn Van Pelt, Laurent Meijer, Kelly Hunt and Khandan Keyomarsi

Low molecular weight (LMW) isoforms of cyclin E are posttranslationally generated in breast cancer cells and are associated with aggressive disease and poor prognosis. In this study, the specificity of LMW cyclin E to cancer cells was determined by measuring cyclin E expression in tumor and non-tumor tissue from 340 breast cancer patients.  Our results reveal the LMW isoforms were detected significantly more frequently in breast tumor tissue than in adjacent non-tumor breast tissues (p<0.0001). The biologic consequences of the LMW isoforms was studied using a non-tumorigenic mammary epithelial cell line transfected with the cyclin E isoforms resulting in increased clonogenicity, the inability to enter quiescence in response to growth factor deprivation and genomic instability compared to the full-length cyclin E. Biochemical differences between the full-length the LMW isoforms were also evident.  Biacore analyses show that the LMW isoforms have more efficient binding to CDK2 compared to full-length cyclin E, which could account for the unique biologic consequences observed with the expression of LMW cyclin E. The LMW isoforms of cyclin E are tumor specific, and are biochemically and biologically distinct from the full-length cyclin E which could provide a novel role in breast cancer progression.

Authors

Hannah Wingate

The University of Texas MD Anderson Cancer Center; Houston, Texas

Agnes Puskas

University of Texas Medical School; Houston, Texas

Mylinh Duong

The University of Texas MD Anderson Cancer Center; Houston, Texas

Tuyen Bui

The University of Texas MD Anderson Cancer Center; Houston, Texas

Dana Richardson

The University of Texas MD Anderson Cancer Center; Houston, Texas

Yanna Liu

The University of Texas MD Anderson Cancer Center; Houston, Texas

Susan L. Tucker

The University of Texas MD Anderson Cancer Center; Houston, Texas

Carolyn Van Pelt

The University of Texas MD Anderson Cancer Center; Houston, Texas

Laurent Meijer

Station Biologique; Roscoff, France

Kelly Hunt

The University of Texas MD Anderson Cancer Center; Houston, Texas

Khandan Keyomarsi Corresponding author: kkeyomar@mdanderson.org

The University of Texas MD Anderson Cancer Center; Houston, Texas