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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 1α-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 1α 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.