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Annals of Oncology Advance Access published online on January 8, 2009
Annals of Oncology, doi:10.1093/annonc/mdn651
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© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

Increased {gamma}-tubulin expression and P16INK4A promoter methylation occur together in preinvasive lesions and carcinomas of the breast

T. Liu, Y. Niu*, Y. Yu, Y. Liu and F. Zhang

Breast Cancer Research Key laboratory of National Education Ministry, Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China

* Correspondence to: Prof. Y. Niu, Breast Cancer Research Key Laboratory of National Education Ministry, Cancer Institute and Hospital, Tianjin Medical University, Huan Hu Xi Road, Ti Yuan Bei, He Xi District, Tianjin 300060, China. Tel: +86-22-23340123-5221; Fax: +86-22-23359337; E-mail: yunniu2000{at}yahoo.com.cn

Background: Loss of p16INK4A due to promoter hypermethylation is correlated with the ability to acquire centrosomal abnormalities in variant human mammary epithelial cells. {gamma}-Tubulin is a highly conserved component of centrosome in most animal cells and {gamma}-tubulin protein overexpression could lead to centrosome aberration.

Materials and methods: A large series of breast premalignant lesions and carcinoma was analyzed. Real-time quantitative PCR and immunohistochemistry were carried out to measure {gamma}-tubulin copy numbers and protein expression. MethyLight and immunohistochemistry were carried out to determine p16INK4A methylation and protein expression.

Results: {gamma}-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 {gamma}-tubulin gene amplification.

Conclusion: {gamma}-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 {gamma}-tubulin gene amplification had a synergistic effect on tumor progression. The synergism might arise as a result of the combined influence that p16INK4a and {gamma}-tubulin have on the G1–S cell cycle checkpoints and centrosome.

ADH–carcinoma sequence, immunohistochemistry, p16INK4A, real-time quantitative PCR, {gamma}-tubulin

Received for publication July 31, 2008. Accepted for publication September 1, 2008.


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