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[Cancer Research 63, 1596-1601, April 1, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Methylation of p16INK4a Promoters Occurs in Vivo in Histologically Normal Human Mammary Epithelia1

Charles R. Holst, Gerard J. Nuovo, Manel Esteller2, Karen Chew, Stephen B. Baylin, James G. Herman and Thea D. Tlsty3

Department of Pathology and University of California at San Francisco Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California 94143-0511 [C. R. H., K. C., T. D. T.]; Ohio State University Medical Center, Columbus, Ohio 43210 [G. J. N.]; and The Johns Hopkins Comprehensive Cancer Center, Baltimore, Maryland 21231 [M. E., S. B. B., J. G. H.]

Cultures of human mammary epithelial cells (HMECs) contain a subpopulation of variant cells with the capacity to propagate beyond an in vitro proliferation barrier. These variant HMECs, which contain hypermethylated and silenced p16INK4a (p16) promoters, eventually accumulate multiple chromosomal changes, many of which are similar to those detected in premalignant and malignant lesions of breast cancer. To determine the origin of these variant HMECs in culture, we used Luria-Delbrück fluctuation analysis and found that variant HMECs exist within the population before the proliferation barrier, thereby raising the possibility that variant HMECs exist in vivo before cultivation. To test this hypothesis, we examined mammary tissue from normal women for evidence of p16 promoter hypermethylation. Here we show that epithelial cells with methylation of p16 promoter sequences occur in focal patches of histologically normal mammary tissue of a substantial fraction of healthy, cancer-free women.




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