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Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer

Alexander, Angela; Karakas, Cansu; Chen, Xian; Carey, Jason P.W.; Yi, Min; Bondy, Melissa; Thompson, Patricia; Cheung, Kwok-Leung; Ellis, Ian O.; Gong, Yun; Krishnamurthy, Savitri; Alvarez, Ricardo H.; Ueno, Naoto T.; Hunt, Kelly K.; Keyomarsi, Khandan


Angela Alexander

Cansu Karakas

Xian Chen

Jason P.W. Carey

Min Yi

Melissa Bondy

Patricia Thompson

Yun Gong

Savitri Krishnamurthy

Ricardo H. Alvarez

Naoto T. Ueno

Kelly K. Hunt

Khandan Keyomarsi


Inflammatory breast cancer (IBC) is a virulent form of breast cancer, and novel treatment strategies are urgently needed. Immunohistochemical analysis of tumors from women with a clinical diagnosis of IBC (n = 147) and those with non-IBC breast cancer (n = 2510) revealed that, whereas in non-IBC cases cytoplasmic cyclin E was highly correlated with poor prognosis (P < 0.001), in IBC cases both nuclear and cytoplasmic cyclin E were indicative of poor prognosis. These results underscored the utility of the cyclin E/CDK2 complex as a novel target for treatment. Because IBC cell lines were highly sensitive to the CDK2 inhibitors dinaciclib and meriolin 5, we developed a high-throughput survival assay (HTSA) to design novel sequential combination strategies based on the presence of cyclin E and CDK2. Using a 14-cell-line panel, we found that dinaciclib potentiated the activity of DNA-damaging chemotherapies treated in a sequence of dinaciclib followed by chemotherapy, whereas this was not true for paclitaxel. We also identified a signature of DNA repair–related genes that are downregulated by dinaciclib, suggesting that global DNA repair is inhibited and that prolonged DNA damage leads to apoptosis. Taken together, our findings argue that CDK2-targeted combinations may be viable strategies in IBC worthy of future clinical investigation.


Alexander, A., Karakas, C., Chen, X., Carey, J. P., Yi, M., Bondy, M., …Keyomarsi, K. (2017). Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer. Oncotarget, 8, 14897-14911.

Journal Article Type Article
Acceptance Date Dec 26, 2016
Online Publication Date Jan 17, 2017
Publication Date Jan 17, 2017
Deposit Date Jan 26, 2017
Publicly Available Date Jan 26, 2017
Journal Oncotarget
Electronic ISSN 1949-2553
Publisher Impact Journals
Peer Reviewed Peer Reviewed
Volume 8
Pages 14897-14911
Keywords Cell cycle, Inflammatory breast cancer, CDK2, Cyclin E, Treatment
Public URL
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