Oncotarget

Research Papers:

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

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

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Oncotarget. 2017; 8:14897-14911. https://doi.org/10.18632/oncotarget.14689

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Abstract

Angela Alexander1,7,*, Cansu Karakas1, Xian Chen1, Jason P.W. Carey1, Min Yi2, Melissa Bondy3, Patricia Thompson4, Kwok Leung Cheung5, Ian O. Ellis5, Yun Gong6, Savitri Krishnamurthy6,7, Ricardo H. Alvarez7,8, Naoto T. Ueno7,8, Kelly K. Hunt2, Khandan Keyomarsi1,*

1Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

2Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

3Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA

4Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA

5University of Nottingham, School of Medicine, Nottingham, UK

6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

7Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA

8Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

*co-corresponding authors

Correspondence to:

Khandan Keyomarsi, email: [email protected]

Angela Alexander, email: [email protected]

Keywords: cell cycle, inflammatory breast cancer, CDK2, cyclin E, treatment

Received: October 12, 2016     Accepted: December 26, 2016     Published: January 17, 2017

ABSTRACT

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.


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