Author: Alexander Kiepas
Publisher:
ISBN:
Category :
Languages : en
Pages :
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"Many physiological processes, including angiogenesis, neurodevelopment and wound healing, rely on the directed movement of cells through the extracellular matrix (ECM). Cell migration is also a fundamental process involved in cancer metastasis. Indeed, proteins that enhance focal adhesion and actin cytoskeletal dynamics are often upregulated in invasive and metastatic cancer cells. In this thesis, we show that the adapter proteins ShcA (p46/52 isoforms) and lipoma-preferred partner (LPP) are required for the migration and invasion of ErbB2-overexpressing breast cancer cells in response to transforming growth factor [beta] (TGF[beta]). Live-cell microscopy techniques reveal that ShcA and LPP are both required for TGF[beta]-enhanced assembly and disassembly of adhesions. Moreover, p46/52ShcA must be phosphorylated on three key tyrosine residues (Y239/Y240/Y313) and LPP must interact with the actin cytoskeleton through its [alpha]-actinin binding domain (ABD) to mediate these effects. Using a BioID proximity labeling approach, we show that p46/52ShcA exists in a complex with various adhesion and actin cytoskeletal proteins, including paxillin and LPP. Total internal reflection fluorescence (TIRF) and 3D super-resolution iPALM microscopy confirm that p46/52ShcA is a novel component of adhesions and its localization to these structures precedes LPP.In addition to acting as a scaffold, the ECM provides biophysical cues that direct cell migration. We demonstrate that LPP is required for ErbB2+ breast cancer cells to sense substrate stiffness. Cells expressing wildtype LPP exhibit enhanced migration rates on intermediate stiffnesses (30-50 kPa), and slower migration rates on soft (10 kPa) and stiff (90kPa) substrates; in contrast, cells lacking LPP expression migrate at a constant speed. ErbB2+ cells also modulate invasive activity based on substrate stiffness. In particular, cells invade maximally on soft (5 kPa) and hard (100 kPa) substrates where migration is significantly reduced. This is the first study to demonstrate that LPP mediates mechanosensitivity in breast cancer cells.Breast cancer is a highly heterogenous disease with considerable cellular, molecular and pathological differences between patients. We find that LPP also plays an important role during TGF[beta]-enhanced migration and invasion of triple-negative breast cancer (TNBC) cells. Human MDA-MB-231 cells with lower levels of LPP expression fail to exhibit TGF[beta]-enhanced migration and invasion. Mouse 4T1 cells, and 4T1 derivatives that preferentially metastasize to the lungs (4T1-526) and live (4T1-2776), also fail to exhibit TGF[beta]-enhanced migration and invasion when LPP expression is reduced. Consequently, 4T1-2776 cells lacking LPP develop fewer liver metastases following splenic injection.Many of experimental results described in this thesis were obtained with live-cell fluorescence microscopy. Fluorescence microscopy provides a convenient, selective and sensitive way to observe live-cell dynamics; however, phototoxicity is a significant limitation of this technique. In this thesis, we show that much of the phototoxicity and photobleaching experienced with live-cell fluorescence imaging occurs as a result of “illumination overhead” (IO). This occurs when a sample is illuminated but fluorescence emission is not being captured by the microscope camera. As a result, we developed a workflow to optimize imaging conditions on any standard microscope. The workflow includes a guide on how to (1) determine the maximum image exposure time for a dynamic process, (2) optimize excitation light intensity, and (3) assess cell health with mitochondrial markers"--
Author: Sandra Yuen-Yun Fok
Publisher:
ISBN:
Category : Breast
Languages : en
Pages : 292
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Author: Marc E. Lippman
Publisher: Springer Science & Business Media
ISBN: 1461539404
Category : Medical
Languages : en
Pages : 455
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Book Description
In Breast Cancer: Cellular and Molecular Biology [Kluwer Academic Pub lishers, 1988], we tried to present an introduction to the emerging basic studies on steroid receptors, oncogenes, and growth factors in the regulation of normal and malignant mammary epithelium. The response to this volume was superb, indicating a tremendous interest in basic growth regulatory mechanisms governing breast cancer and controlling its malignant progres sion. In the two years since its publication, much new and exciting in formation has been published and the full interplay of regulatory mechanisms is now beginning to emerge. We have divided this book into four sections that we hope will unify important concepts and help to crystallize areas of consensus and/or disagreement among a diverse group of basic and clinical scientists working on the disease. The first section is devoted to studies on oncogenes, antioncogenes, proliferation, and tumor prognosis. The first chapter, by Sunderland and McGuire, introduces the characteristics of breast cancer as studied by patho logists to establish prognostic outcome. Of particular interest is a new proto oncogene called HER-2 (or neu), which is rapidly becoming accepted as a valuable new tumor marker of poor prognosis. The second chapter, by Lee Bookstein and Lee, introduces the best known antioncogene, the retinoblas toma antioncogene, whose expression is sometimes lost in breast cancer. Malignant progression appears to be influenced by the balance of proto oncogene and antioncogene expression.
Author: Qifeng Yang
Publisher: Frontiers Media SA
ISBN: 2889747298
Category : Medical
Languages : en
Pages : 274
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Author: Yan Cheng
Publisher: Frontiers Media SA
ISBN: 2832541844
Category : Medical
Languages : en
Pages : 198
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Book Description
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.
Author: Kacey Michelle VanderVorst
Publisher:
ISBN: 9781392727881
Category :
Languages : en
Pages :
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Book Description
Metastasis is a complex, multi-step process whereby cancer cells migrate and invade into surrounding tissues, traverse the vasculature, and colonize metastatic lesions. Cell migration is critical to metastatic dissemination, and aberrant reactivation of developmental migratory pathways is a common theme in cancer biology. Wnt/planar cell polarity (Wnt/PCP) signaling is a non-canonical Wnt signaling pathway that mediates cell migratory events critical to proper embryonic development. Wnt/PCP signaling components are frequently dysregulated in solid tumors, and aberrant pathway activation contributes to tumor cell migratory properties. This dissertation focuses on two distinct observations: (1) that Wnt/PCP signaling mediates carcinoma collective cell migration and invasion, a migratory mode with an emerging role in breast cancer metastasis, and (2) that Wnt/PCP signaling may mediate cell migratory events driven by epithelial-to-mesenchymal transition (EMT), another significant driver of metastatic dissemination. Discussion of each finding is preceded by a review of the literature highlighting recent advances in the contribution of Wnt/PCP signaling to cancer migration and metastasis. Cell migratory modes may be generally classified into two major subtypes: single cell migration or collective cell migration. Importantly, both modes of invasion have been demonstrated to contribute to metastasis, and it is possible that individual tumors invade through one or both mechanisms. Collective migration and invasion have been most extensively studied in breast cancer, where analysis of both mouse and human samples suggest that clusters of primary tumor cells may significantly contribute to critical steps of metastatic dissemination. Here, the contribution of Wnt/Planar cell polarity signaling to breast carcinoma collective cell migration and invasion is described. Components of this pathway are dysregulated in breast cancer, and activating ligand Wnt5a mediates collective cell migration in a Vangl-dependent manner. Wnt5a or Vangl overexpression drives the collective invasion of tumor cells mediated by Keratin14-positive cells at the tips of invading multicellular strands in ex vivo organoid assays. Visualization of Wnt/PCP components and active RhoA GTPase at the leading edge of actively migrating breast cancer cells suggest a model where Wnt/PCP signaling component localization to the leading edge of migrating breast cancer cells regulates the spatio-temporal activity of actin cytoskeletal effectors to govern protrusive membrane activity that drives cellular migration. Epithelial-mesenchymal transition (EMT) has long been considered critical for metastatic dissemination. During EMT, epithelial cells acquire mesenchymal phenotypes characterized by reduced cell-cell adhesion, loss of polarity, and increased migratory and invasive phenotypes. The molecular mechanisms underlying EMT-driven migration and invasion have not been fully characterized. Here, the contribution of Wnt/PCP signaling to EMT-driven migration is described. Activation of the EMT program transcriptionally induces Wnt/PCP signaling components Wnt5a and Fzd7, while simultaneously suppressing Nrdp1, a negative regulator of Wnt/PCP signaling. Suppression of Wnt/PCP signaling impairs EMT-driven cell migration, raising the possibility that Wnt/PCP signaling may be a candidate clinical target for intervention in patients with metastatic disease.
Author: Mohit Kumar Jolly
Publisher: MDPI
ISBN: 3039367242
Category : Medical
Languages : en
Pages : 512
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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: Miao Sun
Publisher:
ISBN:
Category :
Languages : en
Pages : 175
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Book Description
Breast cancer is a serious public health issue, and a full understanding of its etiology and pathophysiology is a primary focus in the field. Molecularly, the combined action of a plethora of factors in multiple pathways is involved in the regulation of the breast tumoriogenic process. Characterization of a more complete spectrum of the molecular factors will provide insights into the development of new and improved diagnostic, prognostic and therapeutic tools for treating breast cancer. To this end, my studies utilize a combination of molecular biology and bioinformatic methods, to uncover the mechanisms underlying the regulation of gene expression and growth in human breast cancer cells. To investigate the molecular crosstalk of the estrogen and c-Jun N-terminal kinase 1 (JNK1) signaling pathways, I monitored the genomic localization of estrogen receptor [alpha] (ER[alpha]) and JNK1 in basal and estrogen-stimulated MCF-7 breast cancer cells. I found that JNK1 binds to the promoter of many genes. ER[alpha] is required for the binding of JNK1 to the estrogen-induced sites, and JNK1 in turn functions as a coregulator of ER[alpha]. The convergence of ER[alpha] and JNK1 at target promoters regulates estrogen-dependent gene expression, as well as downstream estrogendependent cell growth responses. Furthermore, the implication of long noncoding RNAs (lncRNAs) in breast cancer is also coming to light. I developed a computational approach that integrates information from multiple genomic datasets, and generated a comprehensive catalog of 1888 expressed lncRNA genes in MCF-7 cells. Almost half of them are first annotated in this study, and more than a quarter are estrogen-regulated. Close examination revealed many interesting features. Interestingly, cell type-specific expression of lncRNAs predicts the intrinsic molecular subtypes of breast cancer, suggesting its potential utility as prognostic marker. Lastly, by selecting lncRNAs with elevated expression in breast tumors, and whose differential expression across a wide spectrum of tissues and cell types correlates with important cell viability genes, we identified a number of lncRNAs that are required for the normal growth of human breast cancer cells. Collectively, my studies expanded our understanding of the molecular mechanisms underlying breast cancer biology, and suggested new targets for therapeutic interventions.
Author: Robert Brent Dickson
Publisher: Prentice Hall PTR
ISBN:
Category : Medical
Languages : en
Pages : 474
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Book Description
Featuring contributions from expert authors of international standing, this book explores emerging studies on the success and/or failure of chemotherapy in breast cancer. Covers the clinical resistance of breast cancer to treatment; chemo-hormonal reactions; anti-hormonal resistance; multidrug resistance; and fu/antimetabolites. For cancer and hormonal researchers and development scientists in pharmaceuticals and biomedicine. Previously announced in 7/93 PTR Catalog.
Author: Irene Kathryn Guttilla
Publisher:
ISBN:
Category :
Languages : en
Pages : 0
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