title: Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer.
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.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Cansu
authors.initials: C
authors.lastname: Karakas
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xian
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Jason P W
authors.initials: JP
authors.lastname: Carey
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Bondy
authors.affiliation: Department of Pathology, Stony Brook School of Medicine, Stony Brook, New York, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Thompson
authors.affiliation: University of Nottingham, School of Medicine, Nottingham, UK.
authors.forename: Kwok Leung
authors.initials: KL
authors.lastname: Cheung
authors.affiliation: University of Nottingham, School of Medicine, Nottingham, UK.
authors.forename: Ian O
authors.initials: IO
authors.lastname: Ellis
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.|Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.
authors.forename: Savitri
authors.initials: S
authors.lastname: Krishnamurthy
authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ricardo H
authors.initials: RH
authors.lastname: Alvarez
authors.affiliation: Morgan Welch Inflammatory Breast Cancer Research Program and Clinic, Houston, Texas, USA.|Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use; D002453:Cell Cycle; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D003497:Cyclic N-Oxides; D019927:Cyclin E / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007212:Indolizines; D058922:Inflammatory Breast Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000378:metabolism*; D011379:Prognosis; D011726:Pyridinium Compounds / Q000627:therapeutic use; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019086:Bridged Bicyclo Compounds, Heterocyclic; C475820:CCNE1 protein, human; D003497:Cyclic N-Oxides; D019927:Cyclin E; D007212:Indolizines; D015513:Oncogene Proteins; D011726:Pyridinium Compounds; C553669:dinaciclib; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2
keywords: CDK2; cell cycle; cyclin E; inflammatory breast cancer; treatment