Methylation of p16INK4a promoters occurs in vivo in histologically normal human mammary epithelia

Charles R. Holst, Gerard J. Nuovo, Manel Esteller, Karen Chew, Stephen B. Baylin, James G. Herman, Thea D. Tlsty

Research output: Contribution to journalArticlepeer-review

207 Scopus citations


Cultures of human mammary epithelial cells (HMECs) contain a sub-population 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.

Original languageEnglish (US)
Pages (from-to)1596-1601
Number of pages6
JournalCancer Research
Issue number7
StatePublished - Apr 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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