title: Cytoplasmic Cyclin E and Phospho-Cyclin-Dependent Kinase 2 Are Biomarkers of Aggressive Breast Cancer.
abstract: Cyclin E and its co-activator, phospho-cyclin-dependent kinase 2 (p-CDK2), regulate G1 to S phase transition and their deregulation induces oncogenesis. Immunohistochemical assessments of these proteins in cancer have been reported but were based only on their nuclear expression. However, the oncogenic forms of cyclin E (low molecular weight cyclin E or LMW-E) in complex with CDK2 are preferentially mislocalized to the cytoplasm. Here, we used separate nuclear and cytoplasmic scoring systems for both cyclin E and p-CDK2 expression to demonstrate altered cellular accumulation of these proteins using immunohistochemical analysis. We examined the specificity of different cyclin E antibodies and evaluated their concordance between immunohistochemical and Western blot analyses in a panel of 14 breast cell lines. Nuclear versus cytoplasmic staining of cyclin E readily differentiated full-length from LMW-E, respectively. We also evaluated the expression of cyclin E and p-CDK2 in 1676 breast carcinoma patients by immunohistochemistry. Cytoplasmic cyclin E correlated strongly with cytoplasmic p-CDK2 (P < 0.0001), high tumor grade, negative estrogen/progesterone receptor status, and human epidermal growth factor receptor 2 positivity (all P < 0.0001). In multivariable analysis, cytoplasmic cyclin E plus phosphorylated CDK2 (as one variable) predicted breast cancer recurrence-free and overall survival. These results suggest that cytoplasmic cyclin E and p-CDK2 can be readily detected with immunohistochemistry and used as clinical biomarkers for aggressive breast cancer.
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address: ckarakas@mdanderson.org.
authors.forename: Cansu
authors.initials: C
authors.lastname: Karakas
authors.affiliation: Department of Pathology, Baylor College of Medicine, Houston, Texas.
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Tuyen
authors.initials: T
authors.lastname: Bui
authors.affiliation: Department of Pathology and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Aysegul A
authors.initials: AA
authors.lastname: Sahin
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Min
authors.initials: M
authors.lastname: Yi
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Said
authors.initials: S
authors.lastname: Akli
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jolie
authors.initials: J
authors.lastname: Schafer
authors.affiliation: Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Angela
authors.initials: A
authors.lastname: Alexander
authors.affiliation: Department of Pathology and Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Opoku
authors.initials: O
authors.lastname: Adjapong
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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. Electronic address: kkeyomar@mdanderson.org.
authors.forename: Khandan
authors.initials: K
authors.lastname: Keyomarsi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism; D019927:Cyclin E / Q000032:analysis*; D051357:Cyclin-Dependent Kinase 2 / Q000032:analysis*; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019927:Cyclin E; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2