Cell cycle dysregulation influences survival in high risk breast cancer patients.
BACKGROUND
Cell cycle progression is regulated by cyclin dependent kinases (cdk) and cdk inhibitors. Recent immunohistological studies suggested that dysregulation of cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), and p27(kip1) are of prognostic value in patients with breast cancer. Our study represents the first comprehensive immunohistochemical cell cycle marker analysis for cdc25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb in tumor tissue and adjacent benign breast tissue from 69 primarily untreated breast cancer patients.


METHODS
Immunhistochemistry using primary monoclonal antibodies to detect cdc 25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb has been performed.


RESULTS
Sixty-nine patients with untreated, invasive breast cancer (n = 69) were divided into a low/ intermediate and a high risk group according to the St. Gallen 2005 consensus conference. High risk patients (n = 22) had a significantly (p = 0.003) shorter mean and median survival (282.85 weeks; 383.0 weeks, respectively) than low/intermediate risk patients (375.41 weeks; not reached yet, respectively). A subgroup of high risk breast cancer patients characterized in addition by overexpression of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) experienced a shortened mean survival of 222.03, 235.71, 257.25, 239.18, and 261.94 weeks, respectively. Regarding benign breast tissue adjacent to breast cancer tissue, 59.4% of the patients investigated overexpressed cdc25A, 23.2% overexpressed pRb, and 63.2% exerted dysregulation of p27(kip1) while they proved to be negative for immunohistochemical staining regarding all other markers tested.


CONCLUSIONS
The immunohistological analyses of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) have the potential for further refining the risk assessment in patients with untreated breast cancer who belong to the high risk category defined according to the St. Gallen 2005 consensus conference. These cell cycle markers define a subgroup of high risk patients with even higher risk of metastazation and shortened survival. For confirmation a prospective study using standardized laboratory procedures in a larger population is needed.
Königsberg
Robert
R
Third Medical Department, Centre for Oncology and Hematology, CEADDP, Applied Cancer Research, Institution for Translational Research Vienna, and Ludwig Boltzmann-Institute for Applied Cancer Research, Vienna, Austria. rkoenigsberg@yahoo.de
Rögelsperger
Olga
O
Jäger
Walter
W
Thalhammer
Theresia
T
Klimpfinger
Martin
M
De Santis
Maria
M
Hudec
Marcus
M
Dittrich
Christian
C
D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry* / Q000201:enzymology / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000032:analysis*; D049109:Cell Proliferation; D019925:Cyclin A / Q000032:analysis; D056741:Cyclin D; D019927:Cyclin E / Q000032:analysis; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000032:analysis; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D053208:Kaplan-Meier Estimate; D009361:Neoplasm Invasiveness; D016016:Proportional Hazards Models; D016160:Retinoblastoma Protein / Q000032:analysis; D012189:Retrospective Studies; D018570:Risk Assessment; D016896:Treatment Outcome; D020687:cdc25 Phosphatases / Q000032:analysis
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056741:Cyclin D; D019927:Cyclin E; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D047908:Intracellular Signaling Peptides and Proteins; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases