Increased expression of senescence markers P14ARF and p16 INK4a in breast cancer is associated with increased risk of disease recurrence and poor survival outcome

Aims: Breast cancer is a hormonally driven disease. Cellular senescence is an age-related irreversible cell cycle arrest at the G ₁ 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. Methods and 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.