Download or read book Identification of Metastasis Suppressor Signaling Pathways in Breast Cancer written by Miao Sun and published by . This book was released on 2013 with total page 146 pages. Available in PDF, EPUB and Kindle. Book excerpt: Elucidating targets of physiological metastasis suppressors can highlight key signaling pathways leading to tumor invasion and metastasis. To identify downstream targets of the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP), I developed an integrated approach based on statistical analysis of tumor gene expression data combined with experimental validation. In the first part of the thesis, I utilized this approach to identify and validate two novel signaling pathways targeted by RKIP that promote HMGA2-driven metastasis in human breast cancer. RKIP induces and HMGA2 inhibits expression of miR-200b, and miR-200b directly inhibits expression of lysyl oxidase (LOX), leading to decreased invasion. RKIP also inhibits syndecan-2 (SDC2 ) via down-regulation of HMGA2, but this mechanism is independent of miR-200. Depletion of SDC2 induces apoptosis and suppresses breast tumor growth and metastasis in mouse xenografts. The RKIP/LOX/SDC2 signature is prognostic for metastasis-free survival in ER-negative breast cancer patients. To further identify critical downstream targets of HMGA2 in human breast cancer, I did gene and microRNA expression array analyses of human breast cancer cells with depleted HMGA2 expression. In the second part of the thesis, I show that TET1 and HOXA9 are important effectors of HMGA2. Depletion of HMGA2 induces TET1 expression. TET1 binds and demethylates its own promoter as well as the promoters of HOXA genes, stimulating TET1 and HOXA gene expression. Both TET1 and HOXA9 suppress breast tumor growth and metastasis in mouse xenografts, and a gene signature based upon HMGA2, TET1, and HOXA9 expression is prognostic for overall survival in breast cancer patients. These results implicate the HMGA2-TET1-HOXA9 signaling pathway in the epigenetic regulation of breast cancer and highlight the importance of targeting methylation as a potential therapeutic strategy.

Download or read book Identification and Analysis of a New Tumor and Metastasis Suppressor Gene RASAL2 written by Sara Koenig McLaughlin and published by . This book was released on 2013 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: RAS is one of the most commonly mutated genes in human cancer; its aberrant activation drives tumor cell proliferation and survival. However, RAS mutations are rare in some cancers, including breast cancer, even though the Ras pathway is hyperactivated, suggesting that alternative mechanisms deregulate Ras signaling in these settings. The RasGAPs are negative regulators of Ras and, as such, are poised to function as tumor suppressors whose loss might contribute to Ras pathway hyperactivation in cancer. However, the RasGAPs remain an understudied family of genes whose role in cancer has not been fully explored. In this Dissertation I identify a previously uncharacterized RasGAP, RASAL2, as the newest tumor suppressor in this gene family.

Download or read book The Heterogeneity of Cancer Metabolism written by Anne Le and published by Springer. This book was released on 2018-06-26 with total page 186 pages. Available in PDF, EPUB and Kindle. Book excerpt: Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

Download or read book Unravelling Cancer Signaling Pathways A Multidisciplinary Approach written by Kakoli Bose and published by Springer Nature. This book was released on 2019-11-25 with total page 587 pages. Available in PDF, EPUB and Kindle. Book excerpt: Unravelling the intricate cell signalling networks and their significance in cancer poses major intellectual challenge. Keeping this in mind, the book aims at understanding the mechanism of action of different proteins and their complexes in the cancer signalling pathways. Hence, the proposed book that comprises 20 chapters provides a comprehensive introduction on cell signalling, its alterations in cancer, molecules that have been popular targets as well as the ones that are emerging as targets. In addition, it discusses different forms of therapy that are coming up for its treatment. Other than that, a major portion of the book is focused on studying different disciplines at the interface of biology and other areas of science that are being used to understand cancer biology in depth.

Download or read book Signal Transduction in Cancer written by David A. Frank and published by Springer Science & Business Media. This book was released on 2002-12-31 with total page 358 pages. Available in PDF, EPUB and Kindle. Book excerpt: One of the most exciting areas of cancer research now is the development of agents which can target signal transduction pathways that are activated inappropriately in malignant cells. The understanding of the molecular abnormalities which distinguish malignant cells from their normal counterparts has grown tremendously. This volume summarizes the current research on the role that signal transduction pathways play in the pathogenesis of cancer and how this knowledge may be used to develop the next generation of more effective and less toxic anticancer agents. Series Editor comments: "The biologic behavior of both normal and cancer cells is determined by critical signal transduction pathways. This text provides a comprehensive review of the field. Leading investigators discuss key molecules that may prove to be important diagnostic and/or therapeutic targets."

Download or read book Targeting Breast Cancer Transcription driven Signaling Pathways to Improve Therapeutic Response in Triple Negative Breast Cancer written by Melyssa Susann Roberts and published by . This book was released on 2020 with total page 300 pages. Available in PDF, EPUB and Kindle. Book excerpt: Effective treatment for patients with triple negative breast cancer (TNBC) is highly limited by resistance and low treatment response rates. Though extensive research has been conducted to determine molecular mechanisms behind these obstacles, we still have limited understanding of their root causes. It is critical to identify proteins that regulate resistance in order to target these specific drivers that promote cellular reprogramming and cause the notable lack of response of TNBC. This would facilitate the development of improved therapeutic options that would ultimately improve patient survival outcomes. We discovered that expression of LIN9, a mitotic regulator, is required for the maintenance of taxane resistance. LIN9 inhibition, genetically or pharmacologically, restored taxane sensitivity, promoted mitotic progression errors, and led to cell death. However, LIN9 is a scaffolding protein that is not readily druggable, thus we identified a downstream target, NEK2 (NIMA-related Kinase 2) for which there are available inhibitors. We found that NEK2 expression is also required for taxane resistance and that its silencing both restores sensitivity and causes aberrant mitosis. Combination treatment with paclitaxel and a NEK2 inhibitor in vivo caused a significant decrease in tumor volume compared to either drug alone in both sensitive and resistant mouse models. Thus, the LIN9/NEK2 pathway is a driver of taxane resistance that can be therapeutically targeted to reverse resistance. We also discovered the transcription factor and metastasis suppressor KLF4 to be a key mediator of erlotinib response in TNBC cells. Erlotinib is an FDA-approved inhibitor of EGFR, a receptor that mediates a variety of tumorigenic signaling. As EGFR inhibitors have not been highly successful in the clinic, we sought to understand molecular reasons for this lack of response. We discovered that KLF4 inhibits EGFR expression and activity and that its expression increases response to erlotinib. This suggests KLF4 is a key regulator of drug response in TNBC through regulation of EGFR. Lastly, we transitioned our focus of breast cancer mortality from the laboratory bench to populations at risk. We assessed disparities in breast cancer mortality among women that vary with residence at diagnosis between Ohio urban and rural counties. We found that women who reside in rural counties have higher rates of breast cancer mortality than those in urban counties, controlling for age, stage at diagnosis, and race. Many risk factors pose challenges to those in rural areas including unhealthy lifestyles, limited access to healthcare providers, and poverty. This study identified an increased risk of breast cancer mortality in rural counties of Ohio, supporting the need to reduce the level of this disparity. Together, these studies identify critical driver pathways of drug response and resistance that could potentially be targeted in TNBC to improve patient outcomes, as well as identifying specific patient populations that have increased mortality risks.

Download or read book Breast Cancer written by Phuc Van Pham and published by BoD – Books on Demand. This book was released on 2017-04-05 with total page 570 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast Cancer - From Biology to Medicine thoroughly examines breast cancer from basic definitions, to cellular and molecular biology, to diagnosis and treatment. This book also has some additional focus on preclinical and clinical results in diagnosis and treatment of breast cancer. The book begins with introduction on epidemiology and pathophysiology of breast cancer in Section 1. In Section 2, the subsequent chapters introduce molecular and cellular biology of breast cancer with some particular signaling pathways, the gene expression, as well as the gene methylation and genomic imprinting, especially the existence of breast cancer stem cells. In Section 3, some new diagnostic methods and updated therapies from surgery, chemotherapy, hormone therapy, immunotherapy, radiotherapy, and some complementary therapies are discussed. This book provides a succinct yet comprehensive overview of breast cancer for advanced students, graduate students, and researchers as well as those working with breast cancer in a clinical setting.

Download or read book New Developments in Metastasis Suppressor Research written by Paul Jackson and published by Nova Publishers. This book was released on 2007 with total page 340 pages. Available in PDF, EPUB and Kindle. Book excerpt: The spread of cancer cells from their organ of origin to distant tissues is called metastasis. Cancer metastasis is the main cause of death from cancer, and in many cases is difficult to detect or treat. The process by which tumour cells become metastatic is complex and involves many stages, including detachment of cells from the main tumour mass, degradation of the surrounding extra-cellular matrix, invasion into nearby blood vessels, travel and survival through the circulatory system, attachment to a vessel wall, extra-vasation, degradation of the extra-cellular matrix into a distant tissue/organ, and the development of a novel blood supply. In order to accomplish this process, the cells acquire characteristics which are important for each stage. Recently, a class of genes known as metastasis suppressors' has been the subject of intense investigation. For some metastasis suppressor genes, there is strong evidence from both in vitro and in vivo studies to demonstrate key roles in the metastatic process, for others data is much more limited, and their importance uncertain. In this book, chapters are devoted to providing up-to-date summaries of our understanding of individual metastasis suppressor genes. Each is written by a leading authority in the study of that gene. Topics covered include discussions on how each metastasis suppressor was discovered, the mechanisms underlying their loss of expression in tumours and tumour cell lines, their proposed molecular functions, and the consequences to a tumour cell of the loss of this function. This compilation aims to provide, in a single volume, comprehensive information that will be valuable to all scientists working in cancer research, to students needing to understand molecular events that regulate tumour progression and the acquisition of metastasis, and to clinicians who might wish to know more of the roles of potentially new markers for cancer diagnosis and prognosis.

Download or read book Molecular Mechanisms of Drug Resistance And Strategies of Sensitization in Breast Cancer 2nd edition written by Yan Cheng and published by Frontiers Media SA. This book was released on 2024-01-11 with total page 198 pages. Available in PDF, EPUB and Kindle. Book excerpt: Basic scientific background Breast cancer is one of the most common cancer and the most frequent cause of cancer death among women worldwide. Currently, subtyping breast cancers into hormone receptor (HR) positive, human epidermal growth factor receptor-2 overexpressing (HER2+), and triple negative breast cancer (TNBC) is the basis of diagnosing and treating this disease. The main treatment strategies for breast cancer include surgery, endocrine therapy, molecular targeted therapy, chemotherapy, radiotherapy, immunotherapy and gene therapy. However, resistance of breast cancer cells to chemotherapeutic agents, molecular targeted therapies and immunotherapy may occur either intrinsically or de nova, and is often ultimately responsible for treatment failure. Therefore, drug resistance poses a major challenge to breast cancer treatment. Current developments: Drug resistance in breast cancer is a complex clinical condition originating from a wide range of molecular alterations. The development of endocrine therapy resistance is believed to be associated with many cellular changes, such as ESR1 gene mutations, bypassing estrogen signaling pathway and altered tamoxifen metabolism. Meanwhile, changes in immune response, alternation of drug-binding property and downstream pathways are involved in the mechanisms of drug resistance in HER2+ breast cancer. In addition, resistance to chemotherapeutic agents predominantly arises from increased drug efflux and cross resistance. Current studies suggest that treatment strategies and therapeutics have to be designed specifically to each patient in different clinical situations. The use of modern genomic, proteomic and functional analytical techniques has contributed to identify novel genes and signaling networks involved in breast cancer drug resistance. Moreover, the use of high-throughput techniques in combination with bioinformatics and systems biology approaches has aided the interrogation of clinical samples and allowed the identification of molecular signatures and genotypes that predict responses to certain drugs. Despite much progress has been made in the field of breast cancer drug resistance, such as combination therapy and drug-loaded nanoparticles, the complexity and variability of drug resistance mechanism still inevitably lead to the continuous occurrence of drug resistance. Therefore, with the increasing amounts of anti-breast cancer agents, there are now unprecedented opportunities to understand and overcome drug resistance through further research into mechanisms and corresponding strategies, which will help achieve lasting disease control and bring survival benefits to patients with advanced cancer. Papers of interest: The current Research Topic of Frontiers in Pharmacology focuses on publishing Original Research, Review articles and Case Reports focusing on (a) elucidating mechanisms of drug resistance in breast cancer, target mutations, tumor microenvironment, undiscovered genes and signaling pathways; (b) promising drug delivery systems that can enhance the sensitivity of anti- breast cancer agents to various tumors; (c) strategies that can improve patient care during bio-chemotherapeutic treatments; (d) small molecule compounds that are effective against drug-resistant breast tumors (e) biomarkers of chemotherapy resistance in breast cancer patients and (f) in vitro and in vivo models. Guidelines for article of submission: - Authors must stick to the set guidelines for ethical practices by the Frontiers journals. - The main content of the article must have certain innovation and research significance. - The authors should describe the construction method of drug-resistant cell lines when using them for experiments in the article.

Download or read book Metastatic Cancer Clinical and Biological Perspectives written by Rahul Jandial and published by CRC Press. This book was released on 2013-08-08 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Most cancer deaths are a result of metastasis. The spread of a primary tumor to colonize neighboring and distant organs is the relentless endgame that defines the neoplastic process. Patients who have been diagnosed with cancer are treated to prevent both the recurrence of the tumor at the site of origin and metastasis that would re-stage them as advanced stage IV cancer. Historically and still with some types of cancer, stage IV is perceived by patients as “terminal.” Fortunately, recent molecular therapies have extended the lives of patients with advanced cancer and reassuringly people living with metastatic disease increasingly visit our clinics. What is the path forward? Given that the consilience of science and medicine is a dynamic art from which therapies arise, it would be misguided to consider any single work adequate at capturing the horizon for research. So with humility we constructed this text as primer for scientists. It begins with a broad introduction to the clinical management of common cancers. This is intended to serve as a foundation for investigators to consider when developing basic science hypotheses. Unquestionably, medical and surgical care of cancer patients reveals biology and dictates how novel therapeutics will ultimately be evaluated in clinical trials. The second section of this text offers provocative and evolving insights that underscore the breadth of science involved in the elucidation of cancer metastasis biology. The text concludes with information that integrates scientific and clinical foundations to highlight translational research. This book serves as a framework for scientists to conceptualize clinical and translational knowledge on the complexity of disease that is metastatic cancer.

Download or read book Molecular Biology of The Cell written by Bruce Alberts and published by . This book was released on 2002 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Breast Cancer Metastasis and Drug Resistance written by Aamir Ahmad and published by Springer Science & Business Media. This book was released on 2012-11-08 with total page 415 pages. Available in PDF, EPUB and Kindle. Book excerpt: ​This volume comprehensively covers recent prrogress in breast cancer research. In an effort to successfully treat breast cancer, it is imperative to a) fully understand the disease with all its heterogeneity, b) understand the factors that influence the metastasis of breast cancer to distant organs making it lethal and c) understand the underlying processes that lead to the phenomenon of drug-resistance making the disease particularly incurable. The book explores all of these issues, including the phenomenon of epithelial-mesenchymal-transition, cancer stem cells as well as microRNAs in an attempt to better understand the disease in connection to its heterogeneity/metastasis/drug-resistance as well as to propose novel signaling pathways for therapeutic intervention. The profiling of tumors to molecularly classify breast cancers is also investigated so that customized targeted therapies can be developed. ​

Download or read book Integrated Analysis of Breast Cancer Cell Lines Reveals Unique Signaling Pathways written by and published by . This book was released on 2009 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is a heterogeneous disease resulting from the accumulation of genetic defects that negatively impact control of cell division, motility, adhesion and apoptosis. Deregulation in signaling along the EGFR-MAPK pathway is common in breast cancer, though the manner in which deregulation occurs varies between both individuals and cancer subtypes. We were interested in identifying subnetworks within the EGFR-MAPK pathway that are similarly deregulated across subsets of breast cancers. To that end, we mapped genomic, transcriptional and proteomic profiles for 30 breast cancer cell lines onto a curated Pathway Logic symbolic systems model of EGFR-MEK signaling. This model was comprised of 539 molecular states and 396 rules governing signaling between active states. We analyzed these models and identified several subtype specific subnetworks, including one that suggested PAK1 is particularly important in regulating the MAPK cascade when it is over-expressed. We hypothesized that PAK1 overexpressing cell lines would have increased sensitivity to MEK inhibitors. We tested this experimentally by measuring quantitative responses of 20 breast cancer cell lines to three MEK inhibitors. We found that PAK1 over-expressing luminal breast cancer cell lines are significantly more sensitive to MEK inhibition as compared to those that express PAK1 at low levels. This indicates that PAK1 over-expression may be a useful clinical marker to identify patient populations that may be sensitive to MEK inhibitors. All together, our results support the utility of symbolic system biology models for identification of therapeutic approaches that will be effective against breast cancer subsets.

Download or read book Genetic Determinants of Breast Cancer Metastasis written by and published by . This book was released on 1999 with total page 49 pages. Available in PDF, EPUB and Kindle. Book excerpt: Metastasis is a complex phenomenon involving both the activation and inactivation of a number of genes. Although a great deal is known about the types and numbers of genes that are activated or inactivated during metastasis, little is known about which genes are responsible for metastatic susceptibility. Identification and characterization of these genes would provide additional insights into this process, as well as potentially leading to novel therapeutic strategies. To identify inbred mouse strains harboring metastasis suppressors, previously we performed a survey to identify mouse strains that inhibited the ability of a transgene induced mammary tumor to form pulmonary metastases. Two inbred strains, DBA/2J and NZB/B1NJ were shown to significantly suppress the ability of the tumor to disseminate, indicative of the presence of metastasis suppressor genes in those genetic backgrounds. We have performed three independent genetic mapping experiments to determine the approximate genetic location of the metastasis suppressor genes. Our preliminary results suggest that there is at least one gene that is responsible the metastatic suppression, and possibly an unlinked second epistatically interacting gene. We are currently completing the preliminary mapping studies prior to initiating high resolution mapping strategies to further refine the genetic location(s) of the metastatic suppressor gene(s).

Download or read book Systems Biology of Cancer written by Sam Thiagalingam and published by Cambridge University Press. This book was released on 2015-04-09 with total page 597 pages. Available in PDF, EPUB and Kindle. Book excerpt: An overview of the current systems biology-based knowledge and the experimental approaches for deciphering the biological basis of cancer.

Download or read book Molecular Mechanisms of Metastasis Suppression in Human Breast Cancer written by and published by . This book was released on 2000 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Our preliminary data indicated the presence of a breast carcinoma metastasis suppressor genes on human chromosome 11. The goal was to identify and begin characterizing the gene(s) responsible. Two approaches were proposed - (1) introduction of smaller pieces of chromosome 11 into cells with assessment of metastatic potential; and (2) identification of differentially expressed mRNA in metastasis suppressed cells. Progress using Approach #1 was not successful. Approach #2 was successful. We identified three novel cDNAs using differential display which were more highly expressed in the metastasis-suppressed neo11/435 hybrids. Moreover, one of those candidates, BRMS1, significantly suppressed metastasis in two human breast carcinoma cell lines when transfected and constitutively expressed. BRMS1 1 maps to 11q13, a site commonly involved in late-stage breast carcinoma. The mechanism of action appears to be novel, but was not determined during the funding period. In summary, we accomplished the stated ultimate objective for DAMD-17-96-1-6152. Results generated from DAMD-17- 96-1-6152 were used to successfully compete for funding from the National Cancer Institute to follow-up on these exciting findings.

Download or read book Experimental Metastasis Modeling and Analysis written by Anastasia Malek and published by Springer Science & Business Media. This book was released on 2013-12-02 with total page 212 pages. Available in PDF, EPUB and Kindle. Book excerpt: Metastatic dissemination of cancer is a main cause of cancer related deaths, therefore biological mechanisms implicated in metastatic process presents an essential object of cancer research. This research requires creation and utilization of adequate laboratory models. The book describes main approaches to model processes of metastatic cancer dissemination and metastases development. The book is structured in according with various metastatic pathways reflecting molecular specificity of metastatic process as well as anatomical specificity of aria of dissemination. Each chapter is introduced by short discussion of clinical aspects of certain metastatic pathway. Especial attention is paid for methods of visualization, quantification and analysis of the modeled metastases. Additional chapter is devoted to methods of mathematic modeling of tumor spread. The data presented in the book may be helpful for cancer researchers and oncologists.