title: Increased expression of senescence markers p14(ARF) and p16(INK4a) in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome.
abstract: OBJECTIVE
  Breast cancer is a hormonally driven disease. Cellular senescence is an age-related irreversible cell cycle arrest at the G1 phase upon induction. The aim of this study was to characterize the expression patterns of the senescence markers p14(ARF) , p16(INK4a) and p21(WAF1/Cip1) during breast cancer progression in a large patient cohort.
  
  
  RESULTS
  We conducted a retrospective study of 1080 patients with invasive ductal carcinoma, no special type, over an 11-year period. We performed immunohistochemical staining on tissue microarrays that included normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma tissue from each patient. Invasive ductal carcinomas showed higher expression of p14(ARF) and p16(INK4a) but lower expression of p21(WAF1/Cip1) than non-malignant tissues. There were significant correlations of normal, benign, preinvasive and malignant tissues with p14(ARF) , p16(INK4a) and p21(WAF1/Cip1) expression (P < 0.05). Univariate comparison showed a correlation between high p16(INK4a) expression and poor survival (P = 0.000) and an increased risk of relapse (P = 0.000), whereas high p14(ARF) expression correlated only with an increased risk of relapse (P = 0.038). Multivariate analysis showed p16(INK4a) to be an important prognostic factor for overall survival (P = 0.011) and disease-free survival (P = 0.004), with p14(ARF) also being a significant prognostic factor for disease-free survival (P = 0.043). Moreover, patients showing both high p16(INK4a) expression and and high p14(ARF) expression had an adjusted three-fold increased risk of disease recurrence (P < 0.05) and a two-fold increased risk of all-cause-related death (P < 0.05).
  
  
  CONCLUSIONS
  These finding suggest p16(INK4a) expression and p14(ARF) expression may play an important role in the progression of proliferative breast tissue to invasive cancer, and may be useful as prognostic factors.
authors: Discipline of Pathology, School of Medicine, Western Sydney University, Liverpool, NSW, Australia.|Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.
authors: Rahmawati
authors: R
authors: Pare
authors: Discipline of Pathology, School of Medicine, Western Sydney University, Liverpool, NSW, Australia.|Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.|Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW, Australia.
authors: Joo-Shik
authors: JS
authors: Shin
authors: Discipline of Pathology, School of Medicine, Western Sydney University, Liverpool, NSW, Australia.|Ingham Institute for Applied Medical Research, Liverpool, NSW, Australia.|Department of Anatomical Pathology, Liverpool Hospital, Liverpool, NSW, Australia.|Cancer Pathology, Bosch Institute, University of Sydney, Sydney, NSW, Australia.|South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia.
authors: Cheok Soon
authors: CS
authors: Lee
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000401:mortality / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000401:mortality / Q000473:pathology*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000096:biosynthesis*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D046888:Tissue Array Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF
keywords: breast cancer; cellular senescence; p14ARF; p16INK4a