Genetic and Epigenetic Changes in Mammary Epithelial Cells Identify a Subpopulation of Cells Involved in Early Carcinogenesis

  1. H. BERMAN,
  2. J. ZHANG,
  3. Y.G. CRAWFORD,
  4. M.L. GAUTHIER,
  5. C.A. FORDYCE,
  6. K.M. McDERMOTT,
  7. M. SIGAROUDINIA,
  8. K. KOZAKIEWICZ, and
  9. T.D. TLSTY
  1. Department of Pathology and UCSF Comprehensive Cancer Center, University of California at San Francisco,San Francisco, California 94143-0511.

Abstract

Morphologically normal foci of epithelial cells exhibiting p16 inactivation have been found in several tissues and may be precursorsto cancer. Our previous work demonstrates that cells lacking p16INK4A activity exhibit phenotypes associated withmalignancy (Romanov et al. 2001). The acquisition of genomic instability occurs through the activation of telomeric and centrosomaldysfunction. Additionally, the activation of stress pathways such as COX-2 provides these cells with the mutagenicpotential to survive adverse environments as well as the ability to migrate, evade apoptosis and immune surveillance, andsummon sustaining vasculature. Examination of archived tissue from women with DCIS (ductal carcinoma in situ) revealsepithelial cells that overexpress markers of premalignant stress activation pathways and mirror the distinctive expression patternsof these markers observed in vitro. These epithelial cells are found within the premalignant lesion as well as in the fieldof morphologically normal tissue that surrounds the lesion. Here, we show that p16INK4A-silenced vHMEC cells exhibit agene expression profile which is distinct, reproducible, and extends beyond the changes mediated by p16INK4A inactivation.The present work suggests that cells lacking p16INK4A activity exhibit critical activities which allow cells to evade differentiationprocesses that would be expected to terminate proliferation. All of these properties are critical to malignancy. Theseevents may be useful biomarkers to detect the earliest events in breast cancer.

Footnotes

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