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Full-Text Articles in Medicine and Health Sciences
Oncogenic Transformation Of Mammary Epithelial Cells By Transforming Growth Factor Beta Independent Of Mammary Stem Cell Regulation, Karen Dunphy, Jae-Hong Seo, Daniel J. Kim, Amy L. Roberts, Luwei Tao, James Direnzo, Amanda L. Balboni, Giovanna M. Crisi, Mary J. Hagen, Thiruppavai Chandrasekaran, Kelly J. Gauger, Sallie Smith Schneider, D Joseph Jerry
Oncogenic Transformation Of Mammary Epithelial Cells By Transforming Growth Factor Beta Independent Of Mammary Stem Cell Regulation, Karen Dunphy, Jae-Hong Seo, Daniel J. Kim, Amy L. Roberts, Luwei Tao, James Direnzo, Amanda L. Balboni, Giovanna M. Crisi, Mary J. Hagen, Thiruppavai Chandrasekaran, Kelly J. Gauger, Sallie Smith Schneider, D Joseph Jerry
Karen Dunphy
Background: Transforming growth factor beta (TGFβ) is transiently increased in the mammary gland during involution and by radiation. While TGFβ normally has a tumour suppressor role, prolonged exposure to TGFβ can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFβ during involution to determine the persistent effects on premalignant mammary epithelium. Method: CDβGeo cells, a transplantable mouse mammary epithelial cell line, were treated in vitro for 14 days with TGFβ (5 ng/ml). The cells were passaged for an additional …
Oncogenic Transformation Of Mammary Epithelial Cells By Transforming Growth Factor Beta Independent Of Mammary Stem Cell Regulation, Karen A. Dunphy, Jae-Hong Seo, Daniel J. Kim, Amy L. Roberts, Luwei Tao, James Direnzo, Amanda L. Balboni, Giovanna M. Crisi, Mary J. Hagen, Thiruppavai Chandrasekaran, Kelly J. Gauger, Sallie Smith Schneider, D. Joseph Jerry
Oncogenic Transformation Of Mammary Epithelial Cells By Transforming Growth Factor Beta Independent Of Mammary Stem Cell Regulation, Karen A. Dunphy, Jae-Hong Seo, Daniel J. Kim, Amy L. Roberts, Luwei Tao, James Direnzo, Amanda L. Balboni, Giovanna M. Crisi, Mary J. Hagen, Thiruppavai Chandrasekaran, Kelly J. Gauger, Sallie Smith Schneider, D. Joseph Jerry
D. Joseph Jerry
Background: Transforming growth factor beta (TGFβ) is transiently increased in the mammary gland during involution and by radiation. While TGFβ normally has a tumour suppressor role, prolonged exposure to TGFβ can induce an oncogenic epithelial to mesenchymal transition (EMT) program in permissive cells and initiate the generation of cancer stem cells. Our objective is to mimic the transient exposure to TGFβ during involution to determine the persistent effects on premalignant mammary epithelium. Method: CDβGeo cells, a transplantable mouse mammary epithelial cell line, were treated in vitro for 14 days with TGFβ (5 ng/ml). The cells were passaged for an additional …
Transient Pharmacologic Lowering Of Aβ Production Prior To Deposition Results In Sustained Reduction Of Amyloid Plaque Pathology, Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsentein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A. Osborne, Todd E. Golde
Transient Pharmacologic Lowering Of Aβ Production Prior To Deposition Results In Sustained Reduction Of Amyloid Plaque Pathology, Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsentein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A. Osborne, Todd E. Golde
Lisa Minter
Background: Alzheimer’s disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Aβ that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Aβ in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Aβ with a γ-secretase inhibitor (GSI ) for 1–3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M. Results: These data show that reducing …
Radiation Acts On The Microenvironment To Affect Breast Carcinogenesis By Distinct Mechanisms That Decrease Cancer Latency And Affect Tumor Type, Karen Dunphy, D.H. Nguyen, H.A. Oketch-Rabah, I. Illa-Bochaca, F.C. Geyer, J.S. Reis-Filho, J.H. Mao, S.A. Ravani, J. Zavadil, A.D. Borowsky, J.D. Jeryy
Radiation Acts On The Microenvironment To Affect Breast Carcinogenesis By Distinct Mechanisms That Decrease Cancer Latency And Affect Tumor Type, Karen Dunphy, D.H. Nguyen, H.A. Oketch-Rabah, I. Illa-Bochaca, F.C. Geyer, J.S. Reis-Filho, J.H. Mao, S.A. Ravani, J. Zavadil, A.D. Borowsky, J.D. Jeryy
Karen Dunphy
Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent …
Repression Of Mammary Stem/Progenitor Cells By P53 Is Mediated By Notch And Separable From Apoptotic Activity, Karen Dunphy, L. Tao, C. Bigelow, H. Yan, J.D. Jerry
Repression Of Mammary Stem/Progenitor Cells By P53 Is Mediated By Notch And Separable From Apoptotic Activity, Karen Dunphy, L. Tao, C. Bigelow, H. Yan, J.D. Jerry
Karen Dunphy
Breast cancer is the most common tumor among women with inherited mutations in the p53 gene (Li-Fraumeni syndrome). The tumors represent the basal-like subtype, which has been suggested to originate from mammary stem/progenitor cells. In mouse mammary epithelium, mammosphere-forming potential was increased with decreased dosage of the gene encoding the p53 tumor suppressor protein (Trp53). Limiting dilution transplantation also showed a 3.3-fold increase in the frequency of long-term regenerative mammary stem cells in Trp53−/− mice. The repression of mammospheres by p53 was apparent despite the absence of apoptotic responses to radiation indicating a dissociation of these two activities of p53. …
Estrogen And Progesterone Induce Persistent Increases In P53-Dependent Apoptosis And Suppress Mammary Tumors In Balb/C-Trp53+/- Mice, Karen Dunphy, Anneke C. Blackburn, Haoheng Yan, Lauren R. O'Connell, D Joseph Jerry
Estrogen And Progesterone Induce Persistent Increases In P53-Dependent Apoptosis And Suppress Mammary Tumors In Balb/C-Trp53+/- Mice, Karen Dunphy, Anneke C. Blackburn, Haoheng Yan, Lauren R. O'Connell, D Joseph Jerry
Karen Dunphy
Introduction Treatment with estrogen and progesterone (E+P) mimics the protective effect of parity on mammary tumors in rodents and depends upon the activity of p53. The following experiments tested whether exogenous E+P primes p53 to be more responsive to DNA damage and whether these pathways confer resistance to mammary tumors in a mouse model of Li-Fraumeni syndrome. Methods Mice that differ in p53 status (Trp53+/+, Trp53+/-, Trp53-/-) were treated with E+P for 14 days and then were tested for p53-dependent responses to ionizing radiation. Responses were also examined in parous and age-matched virgins. The effects of hormonal exposures on tumor …
Regulation Of Rac1 Activation By The Low Density Lipoprotein Receptor–Related Protein, Zhong Ma, Keena S. Thomas, Donna J. Webb, Radim Moravec, Ana Maria Salicioni, Wendy M. Mars, Steven L. Gonias
Regulation Of Rac1 Activation By The Low Density Lipoprotein Receptor–Related Protein, Zhong Ma, Keena S. Thomas, Donna J. Webb, Radim Moravec, Ana Maria Salicioni, Wendy M. Mars, Steven L. Gonias
Ana Maria Salicioni
The low density lipoprotein receptor–related protein (LRP-1) binds and mediates the endocytosis of multiple ligands, transports the urokinase-type plasminogen activator receptor (uPAR) and other membrane proteins into endosomes, and binds intracellular adaptor proteins involved in cell signaling. In this paper, we show that in murine embryonic fibroblasts (MEFs) and L929 cells, LRP-1 functions as a major regulator of Rac1 activation, and that this activity depends on uPAR. LRP-1–deficient MEFs demonstrated increased Rac1 activation compared with LRP-1–expressing MEFs, and this property was reversed by expressing the VLDL receptor, a member of the same gene family as LRP-1, with overlapping ligand-binding specificity. …