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Loss of p16INK4A due to promoter hypermethylation is correlated with the ability to acquire centrosomal abnormalities in variant human mammary epithelial cells. γ-Tubulin is a highly conserved component of centrosome in most animal cells and γ-tubulin protein overexpression could lead to centrosome aberration.A large series of breast premalignant lesions and carcinoma was analyzed. Real-time quantitative PCR and immunohistochemistry were carried out to measure γ-tubulin copy numbers and protein expression. MethyLight and immunohistochemistry were carried out to determine p16INK4A methylation and protein expression.γ-Tubulin protein expression was concordant with gene amplification; both of them were found to increase with atypical ductal hyperplasia–carcinoma sequence. The median value and positive rate of p16INK4a methylation increased while protein expression displayed a decreasing trend. P16INK4a methylation showed a firm association with γ-tubulin gene amplification.γ-Tubulin gene amplification and the concomitant protein overexpression present not only in invasive carcinoma but also in a significant fraction of atypical hyperplasia and in situ carcinomas. P16INK4a methylation and γ-tubulin gene amplification had a synergistic effect on tumor progression. The synergism might arise as a result of the combined influence that p16INK4a and γ-tubulin have on the G1–S cell cycle checkpoints and centrosome.