Genetic and epigenetic changes in mammary epithelial cells identify a subpopulation of cells involved in early carcinogenesis

H. Berman, J. Zhang, Y. G. Crawford, M. L. Gauthier, C. A. Fordyce, K. M. McDermott, M. Sigaroudinia, K. Kozakiewicz, T. D. Tlsty

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Morphologically normal foci of epithelial cells exhibiting p16 inactivation have been found in several tissues and may be precursors to cancer. Our previous work demonstrates that cells lacking p16INK4A activity exhibit phenotypes associated with malignancy (Romanov et al. 2001). The acquisition of genomic instability occurs through the activation of telomeric and centrosomal dysfunction. Additionally, the activation of stress pathways such as COX-2 provides these cells with the mutagenic potential to survive adverse environments as well as the ability to migrate, evade apoptosis and immune surveillance, and summon sustaining vasculature. Examination of archived tissue from women with DCIS (ductal carcinoma in situ) reveals epithelial cells that overexpress markers of premalignant stress activation pathways and mirror the distinctive expression patterns of these markers observed in vitro. These epithelial cells are found within the premalignant lesion as well as in the field of morphologically normal tissue that surrounds the lesion. Here, we show that p16INK4A-silenced vHMEC cells exhibit a gene 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 differentiation processes that would be expected to terminate proliferation. All of these properties are critical to malignancy. These events may be useful biomarkers to detect the earliest events in breast cancer.

Original languageEnglish (US)
Pages (from-to)317-327
Number of pages11
JournalCold Spring Harbor symposia on quantitative biology
Volume70
DOIs
StatePublished - 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

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