Abstract | INTRODUCTION: Epithelial tumors, including breast cancer, are being identified and treated at earlier stages of tumor development because of technological advances in screening and detection methods. It is likely that early-stage epithelial tumors, such as mammary ductal carcinoma in situ ( DCIS), will be amenable to new and more efficacious diagnostic tests and forms of therapy. However, our limited understanding of the underlying molecular mechanisms of early-stage epithelial tumor growth has hampered the development of new forms treatment and preventative therapy. METHODS: The Raf-MEK1/2-ERK1/2 mitogen-activated protein kinase module is activated by stimuli complicit in mammary neoplastic progression. We have recently demonstrated that the activation of ERK1/2 induces a non-invasive form of motility, where cells can track along the basement membrane and adjacent epithelial cells, but do not become invasive over time, using real-time imaging of a mammary epithelial organotypic culture model. Using this novel approach combined with traditional biochemical techniques, we have analyzed at the molecular level how ERK1/2 induces this new non-invasive form of motility as well as proliferation and cell survival. RESULTS: We find that the activation of Raf:ER in the differentiated epithelium of fully formed acini promotes proliferation and cell survival, which are characteristic features of pre-invasive DCIS lesions. The activation of ERK1/2 correlated with induction of c-Fos, a transcriptional regulator of proliferation and reduced expression of the pro-apoptotic BH3-only protein BIM. Both ERK1/2 and PI-3 kinase-dependent effector pathways were required for activated Raf:ER to reduce expression of p27 and promote proliferation. In addition, PI-3K activity was necessary for the induction of non-invasive motility induced by ERK1/2. CONCLUSIONS: ERK1/2 activation is sufficient to induce cell behaviors in organotypic culture that could promote recurrent and invasive growth in DCIS patients. Interestingly, PI-3K activity is necessary for two of these behaviors, proliferation and cell motility. Collectively, our results suggest that the relationship between the activity state of the ERK1/2 and PI-3K signaling pathways and recurrent growth in DCIS patients should be investigated.
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Authors | Gray W Pearson, Tony Hunter |
Journal | Breast cancer research : BCR
(Breast Cancer Res)
Vol. 11
Issue 3
Pg. R29
( 2009)
ISSN: 1465-542X [Electronic] England |
PMID | 19457236
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Phosphatidylinositol 3-Kinases
- Mitogen-Activated Protein Kinase 1
- Mitogen-Activated Protein Kinase 3
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Topics |
- Apoptosis
- Breast
(metabolism)
- Cell Line
- Cell Movement
- Cell Proliferation
- Cell Survival
- Disease Progression
- Epithelium
(metabolism, pathology)
- Gene Expression Regulation, Enzymologic
- Humans
- MAP Kinase Signaling System
- Microscopy, Fluorescence
(methods)
- Mitogen-Activated Protein Kinase 1
(metabolism)
- Mitogen-Activated Protein Kinase 3
(metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
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