Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia.
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 p16(INK4a) (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.
Holst
Charles R
CR
Department of Pathology and University of California at San Francisco Comprehensive Cancer Center 94143-0511, USA.
Nuovo
Gerard J
GJ
Esteller
Manel
M
Chew
Karen
K
Baylin
Stephen B
SB
Herman
James G
JG
Tlsty
Thea D
TD
D001940:Breast / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D011401:Promoter Regions, Genetic
D019941:Cyclin-Dependent Kinase Inhibitor p16