p16 ^INK4a expression and breast cancer risk in women with atypical hyperplasia

p16, a nuclear protein encoded by the p16 ^INK4a gene, is a regulator of cell-cycle regulation. Previous studies haveshownthat expression ofp16in tissue biopsies of patients with ductal carcinomain situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki-67 and COX-2. Here, we evaluated how expression of p16 in breast tissue biopsies of women with atypical hyperplasia (AH), a putative precursor lesion to DCIS, is associated with subsequent developmentof cancer. p16expression was assessed byimmunohistochemistry in archival sections from 233 women with AH diagnosed at the Mayo Clinic. p16 expression in the atypical lesions was scored by percentage of positive cells and intensity of staining. We also studied coexpression of p16, with Ki-67 and COX-2, biomarkers of progression in AH. Risk factor and follow-up data were obtained via study questionnaire and medical records. Forty-seven patients (20%) developed breast cancer with a median follow-up of 14.5 years. Staining of p16 was increased in older patients relative to younger patients (P < 0.0025). Although risk of developing breast cancer was not associated with increased p16 expression, joint overexpressionof Ki-67andCOX-2was found to convey stronger risk of breast cancer in the first 10 years after diagnosis as compared with one negative marker (P < 0.01). However, the addition of p16 levels did not strengthen this association. p16 overexpression, either alone or in combination with COX-2 and Ki-67, does not significantly stratify breast cancer risk in women with AH.