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INK4a Gene Expression and Methylation in Primary Breast Cancer: Overexpression of p16^INK4a Messenger RNA Is a Marker of Poor Prognosis¹

Cancer Research Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Darlinghurst, Sydney, New South Wales 2010, Australia [R. H., E. A. M., R. L. S.]; Department of Surgery, City Hospital, Nottingham NG5 1PB, United Kingdom [R. D. M., F. S. K., R. W. B., J. F. R. R.]; and Tenovus Cancer Research Centre, Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3XF, United Kingdom [R. I. N.]

Frequent deletions or mutations of the INK4 gene, which encodes the cyclin-dependent kinase 4 inhibitor p16^INK4a, have been documented in various human cancers, but little is known about the role of this tumor suppressor gene in primary breast cancer. We examined p16^INK4a mRNA expression and its relationship with cyclin D1 and estrogen receptor (ER) expression in 314 primary breast cancers using Northern blots probed with a p16 exon 1-specific cDNA. Tumor samples overexpressing p16^INK4a were predominantly ER negative with low levels of cyclin D1. Cyclin D1 and ER mRNA levels in the high p16^INK4a expressers were significantly lower than those in the remainder of the population (P = 0.0001). Furthermore, the mean p16^INK4a mRNA level in the ER-negative tumors was significantly higher than that in the ER-positive group (P = 0.0001). Because the INK4 gene is frequently inactivated by de novo methylation, we investigated the frequency of INK4a exon 1 methylation in a subset of 120 primary breast cancers using methylation-specific PCR; 24 of these were methylated. These findings indicate that high expression of p16^INK4a and reduced expression due to de novo INK4a methylation are frequent events in primary breast cancer. In a subset of 217 patients for whom detailed clinical data were available, high p16^INK4a mRNA expression was associated with high tumor grade (P = 0.006), 4 axillary lymph node involvement (P = 0.004), ER negativity (P = 0.0001), and increased risk of relapse (P = 0.006). The significant negative correlation between p16^INK4a and ER gene expression raises issues regarding their functional interrelationships and whether high p16^INK4a expression may be associated with a lack of hormone responsiveness in breast cancer.

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