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Breast Cancer Research

, 7:P3.04 | Cite as

Cooperation between extracellular signaling and intracellular Ras activation leads to immortalization and epithelial-to-mesenchymal transition of variant human mammary epithelial cells

  • N Dumont
  • YG Crawford
  • P Reynolds
  • TD Tlsty
Poster Presentation
  • 950 Downloads

Keywords

Normal Tissue Stromal Cell Distinguishing Characteristic Early Event Transformation Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Our laboratory has previously identified a rare subpopulation of variant human mammary epithelial cells (vHMEC) that have the capacity to propagate beyond an in vitro proliferation barrier and accumulate multiple chromosomal changes [1]. These cells contain hyper-methylated and silenced p16(INK4a) (p16) promoters and overexpress COX-2. We found evidence that cells with these characteristics exist in disease-free women in morphologically normal tissue [2]. Furthermore, these distinguishing characteristics have also been found in DCIS lesions, indicating that these cells are very relevant to the carcinogenic process. In order to investigate the molecular mechanisms required for these cells to progress to a malignant phenotype, we examined the effect of oncogenic stress on the transformation of vHMEC by introducing constitutively active Ha-Ras V12 into these cells. Consistent with the idea that vHMEC are already engaged in the transformation process, upon exposure to oncogenic stress vHMEC failed to undergo a proliferative arrest as seen in normal fibroblasts or normal epithelium. We have used this model system to examine the early events that control expression of tumorigenic phenotypes in these cells. We find that critical interactions between stromal cells and initiated epithelial cells are necessary for the manifestation of specific tumorigenic phenotypes such as epithelial-to-mesenchymal transition.

References

  1. 1.
    Romanov SR, Kozakiewicz BK, Holst CR, Stampfer MR, Haupt LM, Tlsty TD: Normal human mammary epithelial cells spontaneously escape senescence and acquire genomic changes. Nature. 2001, 409: 633-637. 10.1038/35054579.CrossRefPubMedGoogle Scholar
  2. 2.
    Holst CR, Nuovo GJ, Esteller M, Chew K, Baylin SB, Herman JG, Tlsty TD: Methylation of p16(INK4a) promoters occurs in vivo in histologically normal human mammary epithelia. Cancer Res. 2003, 63: 1596-1601.PubMedGoogle Scholar

Copyright information

© BioMed Central 2005

Authors and Affiliations

  • N Dumont
    • 1
  • YG Crawford
    • 1
  • P Reynolds
    • 1
  • TD Tlsty
    • 1
  1. 1.Department of Pathology and Comprehensive Cancer CenterUniversity of California at San FranciscoCaliforniaUSA

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