TY - JOUR
T1 - PI-3 kinase activity is necessary for ERK1/2-induced disruption of mammary epithelial architecture
AU - Pearson, Gray W.
AU - Hunter, Tony
N1 - Funding Information:
The authors thank Gina Yanochko and members of the Hunter laboratory for useful discussions. The vector pBABE-Raf:ER was a gift from Michael White and Ron Bumeister (University of Texas Southwestern Medical Center at Dallas, USA) and pCLNRX-H2B:GFP was a gift from Ee Tsin Wong and Geoff Wahl (Salk Institute). The work was supported by grants T32CA009370 and a Genentech Foundation Fellowship (to GWP), and CA14195 and CA82683 (to TH) from the National Cancer Institute. TH is a Frank and Else Schilling American Cancer Society Research Professor.
PY - 2009/5/20
Y1 - 2009/5/20
N2 - 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.
AB - 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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U2 - 10.1186/bcr2259
DO - 10.1186/bcr2259
M3 - Article
C2 - 19457236
AN - SCOPUS:74049107405
SN - 1465-5411
VL - 11
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 3
M1 - R29
ER -