p16INK4a Expression and Breast Cancer Risk in Women with Atypical Hyperplasia

Abstract

p16, a nuclear protein encoded by the p16INK4a gene, is a regulator of cell cycle regulation. Previous studies have shown that expression of p16 in tissue biopsies of patients with ductal carcinoma in situ (DCIS) is associated with increased risk of breast cancer, particularly when considered in combination with other markers such as Ki67 and COX2. 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 development of cancer. p16 expression was assessed by immunohistochemistry in archival sections from 233 women with AH diagnosed at the Mayo Clinic. p16 expression in the atypical lesions was scored by percent of cells positive and intensity of staining. We also studied coexpression of p16, with Ki67 and COX2, 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). While risk of developing breast cancer was not associated with increased p16 expression, joint overexpression of Ki67 and COX2 was found to convey stronger risk of BC in the first 10 years after diagnosis as compared to 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 COX2 and Ki67, does not significantly stratify breast cancer risk in women with AH.

MicroRNA‐137 promoter methylation in oral lichen planus and oral squamous cell carcinoma

“…It has clearly been demonstrated that a decline in p16 expression increases the risk of developing a variety of cancers, and aberrant promoter methylation is considered to be a common way in the inactivation of p16 . Inactivation of p16 and associated promoter methylation has been considered a robust biomarkers for oral cancer and other types of human cancers . In the present study, p16 promoter methylation was detected in 5 of 20 (25%) patients with OLP, and 6 of 12 (50%) patients with OSCC in contrast to none of normal subjects.…”

Stage of Breast Cancer Progression Influences Cellular Response to Activation of the WNT/Planar Cell Polarity Pathway

“…In 21PT, this was associated with a significant increase in AP-1 activity, whereas AP-1 activity, already higher in 21NT cells, showed no change in response to WNT5A. Increased COX-2 expression has been previously associated with increased propensity of DCIS (or ADH) to progress to invasion, particularly when seen in association with increased proliferation (Ki-67 index), and in the case of DCIS, with high p16404142. This has been suggested to be a reflection of an altered stress response in cells more likely to progress.…”

Increased expression of senescence markers p14ARF and p16INK4a in breast cancer is associated with an increased risk of disease recurrence and poor survival outcome

“…To date, increased p16 INK4a expression in both premalignant and malignant tissues has been seen in several other human cancers, including esophageal and prostate carcinoma . Pathophysiologically, overexpression of senescence markers in a tumour cell may indicate that the tumour cell has been activated to enter the senescence programme, but it may also reflect disruption of a downstream mediator of the regulatory pathway …”