Loss of p16 super(INK4) Expression by Methylation Is Associated with Lifespan Extension of Human Mammary Epithelial Cells

Inactivation of p16 super(INK4) tumor suppressor gene function is frequently observed in breast cancer. We examined p16 super(INK4) expression in human mammary epithelial cell (HMEC) cultures established from four normal donors. Normal HMECs divide a limited number of times before proliferation ceas...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1998-08, Vol.58 (16), p.3508-3512
Main Authors: Huschtscha, LI, Noble, J R, Neumann, A A, Moy, EL, Barry, P, Melki, J R, Clark, S J, Reddel, R R
Format: Article
Language:English
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Summary:Inactivation of p16 super(INK4) tumor suppressor gene function is frequently observed in breast cancer. We examined p16 super(INK4) expression in human mammary epithelial cell (HMEC) cultures established from four normal donors. Normal HMECs divide a limited number of times before proliferation ceases in a state referred to as selection (or M sub(0)). The cell subpopulation that emerges spontaneously from selection undergoes a further limited period of proliferation before senescence. By immunofluorescence and Western blot analysis of four independent cultures, we have shown loss of p16 super(INK4) expression in postselection HMECs. In contrast, p16 super(INK4) was present in both early and late passage fibroblasts from the same individuals. Bisulfite genomic sequencing revealed extensive methylation of the p16 super(INK4) CpG island in post- but not preselection cells. Thus, the extended period of growth observed in postselection HMECs is associated with hypermethylation of the p16 super(INK4) CpG island and loss of p16 super(INK4) expression. Although postselection HMECs are widely considered to be normal, these data indicate that they have sustained an epigenetic alteration.
ISSN:0008-5472