Prognostic Roles and Regulation of Smad-mediated TGF-beta Signalling in Breast Cancer PDF Download
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Author: Jimin Guo Publisher: ISBN: Category : Languages : en Pages :
Book Description
"A canonical Transforming Growth Factor Beta (TGF[beta]) signalling pathway, mediated through Smad2, Smad3 and Smad4 proteins, plays context-dependent roles in mammary tumorigenesis and breast cancer progression. These roles vary from maintaining mammary tissue homeostasis to promoting breast cancer metastasis. In the studies presented in this thesis, my colleagues and I take both a computational approach and an experimental approach to address the implications of TGF[beta]-Smad signalling in human breast cancer and its cross talk with Angiotensin II pathway. Our computational study results in a Decision Tree classification model that uses standardized immunohistochemistry (IHC) scores and breast cancer disease characteristics to predict whether a patient will develop early breast cancer relapse. It reveals pathological nodal status, stroma percentage in tumor core and percentages of tumor cells expressing TGF[beta]/Smad signalling components as determinant factors for early breast cancer relapse prediction. Our experimental study identifies a novel positive feedback mechanism downstream of TGF[beta] in breast cancer cells, mediated through Breast Cancer Anti-Estrogen Resistance 3 (BCAR3). We show that BCAR3 inhibits the TGF[beta]/Smad signalling pathway and biological responses to TGF[beta] in breast cancer cells. TGF[beta], in term, down regulates endogenous BCAR3 protein level to mediate a positive feedback loop. In parallel to these studies, we also further characterize a previously identified signalling mechanism in our laboratory, namely TGF[beta]-induced expression of G protein coupled receptor kinase 2 (GRK2). We show that TGF[beta] antagonizes Angiotensin II (Ang II)-induced mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells. Altogether, our studies extend the current knowledge on the TGF[beta]-Smad signalling in 3 dimensions: its prognostic value in breast cancer, its intracellular regulation and its crosstalk with other signalling pathway." --
Author: Jimin Guo Publisher: ISBN: Category : Languages : en Pages :
Book Description
"A canonical Transforming Growth Factor Beta (TGF[beta]) signalling pathway, mediated through Smad2, Smad3 and Smad4 proteins, plays context-dependent roles in mammary tumorigenesis and breast cancer progression. These roles vary from maintaining mammary tissue homeostasis to promoting breast cancer metastasis. In the studies presented in this thesis, my colleagues and I take both a computational approach and an experimental approach to address the implications of TGF[beta]-Smad signalling in human breast cancer and its cross talk with Angiotensin II pathway. Our computational study results in a Decision Tree classification model that uses standardized immunohistochemistry (IHC) scores and breast cancer disease characteristics to predict whether a patient will develop early breast cancer relapse. It reveals pathological nodal status, stroma percentage in tumor core and percentages of tumor cells expressing TGF[beta]/Smad signalling components as determinant factors for early breast cancer relapse prediction. Our experimental study identifies a novel positive feedback mechanism downstream of TGF[beta] in breast cancer cells, mediated through Breast Cancer Anti-Estrogen Resistance 3 (BCAR3). We show that BCAR3 inhibits the TGF[beta]/Smad signalling pathway and biological responses to TGF[beta] in breast cancer cells. TGF[beta], in term, down regulates endogenous BCAR3 protein level to mediate a positive feedback loop. In parallel to these studies, we also further characterize a previously identified signalling mechanism in our laboratory, namely TGF[beta]-induced expression of G protein coupled receptor kinase 2 (GRK2). We show that TGF[beta] antagonizes Angiotensin II (Ang II)-induced mitogen-activated protein kinase (MAPK) activation in vascular smooth muscle cells. Altogether, our studies extend the current knowledge on the TGF[beta]-Smad signalling in 3 dimensions: its prognostic value in breast cancer, its intracellular regulation and its crosstalk with other signalling pathway." --
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
The goal of my studies under the BCRP fellowship is to understand the role of the Smad proteinS and the TGF-beta signal transduction pathways in breast cancer cell proliferation, tumor progression, and prognosis. In the past nine months, I have focused on identifying intracellular molecules and transcription factors that might be involved in the TGF-beta signal transduction pathway. Using both genetic and biochemical approaches, I have successfully isolated a few key molecules that are either mediator of the TGF-beta induced transcriptional response or suppressors of the TGF-beta signal pathways. Future studies will be focused on understanding the detail mechanism of how the molecules interplay in mediating TGF-beta signaling and the significance of these interactions in tumor cell proliferation, progression, and prognosis.
Author: Joshua P. Frederick Publisher: ISBN: Category : Languages : en Pages : 32
Book Description
The ability of transforming growth factor-beta (TGF-beta) to potently suppress the proliferation of normal breast epithelial cells may be central to its putative role in tumor suppression of early stage breast cancers. Thus, the elucidation of the mechanisms by which TGF-beta is able to exert these effects is relevant to the further understanding of breast cancer initiation and possibly prevention. The purpose of these studies is to further define the role of the Smads as TGF-beta-activated transcriptional regulators with particular attention to target genes involved in cellular growth inhibition, and thus, genes potentially involved in the tumor suppression of early breast cancers. The proto- ohcogene c-Myc is repressed by TGE-beta and this repression is paramount for the manifestation of TGE-beta mediated growth arrest of epithelial cells. We have shown that Smad3 is required for both TGF-beta induced c-Myc repression and subsequently growth arrest in epithelial cells. The transcriptional repression of c-Myc is dependent on Smad3 binding to a novel Smad binding element within the TGE-beta Inhibitory Element (TIE) of the c-Myc promoter, termed a Repressive Smad Binding Element (ESBE) . In conclusion, we have established Smad3 as an essential component of TGF-beta induced growth inhibition and contributed to the understanding of how this growth arrest program is initiated.
Author: Publisher: ISBN: Category : Languages : en Pages : 57
Book Description
Transforming growth factor-beta (TGF-beta) is a potent growth inhibitory polypeptide hormone. Although the loss of this negative proliferative signal is often seen in the deregulated growth of early cancer formation, the TGF-beta mediated intracellular pathways that control cell growth remain largely unknown We propose three aims to 1) elucidate the functional role of Smads in TGF-beta signaling, 2) assess their contribution in regulating cell proliferation and 3) to provide evidence that Smad3 acts in vivo as tumor suppressor of early breast cancer formation. In this first year of funding, we have provide evidence that the Smads are specific sequence DNA-binding proteins, and functionally interact wit other transcription factors and the p300/CBP coactivator family of proteins to coordinate disparate pathways in the regulation of specific genes. Towards the goal of the second aim, we have first demonstrated that Smad3 is an essential component of TGF-beta mediated growth inhibition in fibroblast and epithelial cells. The last aim of providing evidence that Smad3 can act as an in vivo breast tumor suppressor will be completed with the use of the Smad3 null mouse model, carcinogen treatment and crossing into other geneticall defined mouse models that are predisosed to breast cancer formation.
Author: Aristidis Moustakas Publisher: Springer Science & Business Media ISBN: 4431544097 Category : Science Languages : en Pages : 463
Book Description
Transforming growth factor-β (TGF-β) is a secreted polypeptide with multifunctional properties manifested during embryonic development, adult organ physiology, and pathobiology of major diseases, including cancer and fibrotic and cardiovascular diseases. The signaling pathway of TGF-β now is rather well understood. Continuing revelations in the mechanisms of action of TGF-β provide specific mechanistic examples of how human cells lose their controlled function and behave wrongly during the development of diverse diseases. Equally important, however, is the current promise of exploiting the TGF-β pathway in combating human disease. This book comprehensively covers major areas of human disease where the involvement of TGF-β is firmly established. Simultaneously, the book highlights major gaps in knowledge and the future directions of research that can benefit human medical science. The core set of diseases where TGF-β action is well documented and are included in the book are cancer and cardiovascular and fibrotic disorders. The central aim of the book is to stimulate young scientists to enter the prolific TGF-β field and find new solutions to the problems remaining in this area of study. For this purpose the book provides authoritative educational chapters that furnish a good introduction to the field for young doctoral students, postdocs, and clinical fellows. The book also serves as a valuable reference for the aficionados in the field, who can find accessible and well-illustrated material for their teaching and lecturing activities, via which the importance of TGF-β biology is disseminated to the world of science and to the public.
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
The overall goal of this research project is to explore the roles of TGF-beta and components of its signaling pathways in the initiation, progression and metastasis of breast adenocarcinomas through an investigation of the disregulation of TGF-beta signal transduction. Last year, we identified and isolated three cDNAs encoding members of the Smad family and studied the TGF-beta induced phosphorylation of these molecules in a normal mammary epithelial cell line. Subsequently, we have focused on the functional role of Smad3 and Smad4 as tumor suppressors in mediating the TGF-beta signal in transactivating downstream target genes. We have also continued our investigation on the mechanism by which TGF-beta activates the expression of cyclin-dependent kinase inhibitor p15 gene in MCF7 cells as well as the importance of a paracrine loop mediated by the interactions between mammary epithelial and fibroblst cells. Results from further analysis in these directions will not only significantly contribute to an understanding of the molecular events leading to breast carcinogenesis, but also aid in the development of new therapeutics for breast cancer.
Author: Mohit Kumar Jolly Publisher: MDPI ISBN: 3039367242 Category : Medical Languages : en Pages : 512
Book Description
Recent studies have highlighted that epithelial-mesenchymal transition (EMT) is not only about cell migration and invasion, but it can also govern many other important elements such as immunosuppression, metabolic reprogramming, senescence-associated secretory phenotype (SASP), stem cell properties, therapy resistance, and tumor microenvironment interactions. With the on-going debate about the requirement of EMT for cancer metastasis, an emerging focus on intermediate states of EMT and its reverse process mesenchymal-epithelial transition (MET) offer new ideas for metastatic requirements and the dynamics of EMT/MET during the entire metastatic cascade. Therefore, we would like to initiate discussions on viewing EMT and its downstream signaling networks as a fulcrum of cellular plasticity, and a facilitator of the adaptive responses of cancer cells to distant organ microenvironments and various therapeutic assaults. We hereby invite scientists who have prominently contributed to this field, and whose valuable insights have led to the appreciation of epithelial-mesenchymal plasticity as a more comprehensive mediator of the adaptive response of cancer cells, with huge implications in metastasis, drug resistance, tumor relapse, and patient survival.
Author: Rik Derynck Publisher: CSHL Press ISBN: 0879697520 Category : Transforming growth factors-beta Languages : en Pages : 1108
Book Description
Transforming growth factor-[beta] (TGF-[beta]), identified nearly three decades ago, is a secreted polypeptide that functions in critical cell cycle processes, including cellular proliferation, differentiation, and development: It belongs to a large protein family that, in humans, contains 33 members, including activins, inhibins, bone morphogenetic proteins, growth and differentiation factors, and Mullerian inhibiting substance. This volume draws on the world's leading laboratories to comprehensively cover all aspects of the biology of TGF-[beta] and related factors. In addition to providing historical and background information, it describes the cell biology and signaling pathways of TGF-[beta] members in detail, including the roles of TGF-[beta] factors in the development and physiology of humans and model organisms. The last few chapters are devoted to the role of TGF-[beta] members in cancer and other diseases, as well as the possibilities for therapeutics based on knowledge of signaling pathways and macromolecular structures. It serves as a comprehensive reference work for both specialists and researchers less familiar with the field.
Author: Boris Pasche Publisher: Springer Science & Business Media ISBN: 1441960333 Category : Medical Languages : en Pages : 119
Book Description
Cancer Genetics is a collection of chapters covering the key recent developments in cancer genetics which have an impact on clinical care. The target audience will be physicians and scientists who need to be apprised on the most recent developments in the field.
Author: Douglas B. Evans Publisher: Springer Science & Business Media ISBN: 0387216006 Category : Medical Languages : en Pages : 413
Book Description
The MD Anderson Solid Tumor Oncology series presents cutting-edge surgical treatment and medical therapy for specific sites. This volume, Pancreatic Cancer, addresses epidemiology and molecular biology, inherited syndromes, staging, surgical techniques, multimodality therapy, and emerging therapies. The individual chapters focus on narrow, specific topics to produce a reference work of value to those interested in pancreatic cancer from a clinical and translational research perspective. A must-have for surgical oncologists and general surgeons.
Author: Jimin Guo
Author: Jimin Guo
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Author: Joshua P. Frederick
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Author: Aristidis Moustakas
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Author: Mohit Kumar Jolly ![The TGF-[beta] Family PDF](https://books.google.com/books/content/images/frontcover/QW5xq75p5gYC?fife=w80-h100)
Author: Rik Derynck
Author: Boris Pasche
Author: Douglas B. Evans