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Erschienen in: Breast Cancer Research 2/2005

01.06.2005 | Poster Presentation

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

verfasst von: N Dumont, YG Crawford, P Reynolds, TD Tlsty

Erschienen in: Breast Cancer Research | Sonderheft 2/2005

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Excerpt

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. …
Literatur
1.
Zurück zum Zitat 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.CrossRefPubMed 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.CrossRefPubMed
2.
Zurück zum Zitat 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.PubMed 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.PubMed
Metadaten
Titel
Cooperation between extracellular signaling and intracellular Ras activation leads to immortalization and epithelial-to-mesenchymal transition of variant human mammary epithelial cells
verfasst von
N Dumont
YG Crawford
P Reynolds
TD Tlsty
Publikationsdatum
01.06.2005
Verlag
BioMed Central
Erschienen in
Breast Cancer Research / Ausgabe Sonderheft 2/2005
Elektronische ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr1126

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