Download or read book Evolution in Mammary Cancer written by Maryknoll Linscott and published by . This book was released on 2024 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Breast cancer, a highly heterogeneous disease, is a product of dynamic variation and selection of mutant clones. The continuous evolution of breast tumor cells has important implications for patient outcomes due to its impacts on treatment response, resistance, and relapse. While a wealth of studies has been conducted on the genetic and epigenetic aberrations that confer a fitness advantage to tumor cells, the sources of selective pressure remain to be understood. Using various clinically relevant mouse models of breast cancer, this dissertation investigates whether and how three factors, which are not mutually exclusive, drive the selection of genetically distinct breast tumor clones: the source of oncogenic signaling (namely, the specific oncogene sustaining an activating mutation); the context of oncogenic signaling (namely, the reproductive history of the mammary cell undergoing transformation); and the strength of oncogenic signaling (as determined by oncogene expression levels). In the first set of experiments directed at modeling breast cancer as a multistage disease, we evaluated how clinically relevant oncogenes Myc and PIK3CA shape the progression of premalignant clones to mammary tumors. By using a well-studied carcinogen, DMBA (7,12-Dimethylbenz[a]anthracene), stereotypical Hras, Kras, and Nras mutations (exons 12, 13, and 61) were randomly introduced in our mouse models. Mice were engineered for mammary-specific, doxycycline (Dox)-inducible expression of either Myc (iMyc mice) or PIK3CAH1047R (iPIK mice). However, despite the introduction of possibly innumerable mutations in the entire organism, only mammary tumors were observed in our studies. These tumors only arose when Myc and PIK3CAH1047R were individually expressed in the mammary glands of our mouse models, which signifies that the tumors occurred in a stepwise fashion. Notably, a different set of Ras-initiated cells comprised the dominant population in Myc- versus PIK3CAH1047R-driven tumors, which suggests that each oncogene prefers to cooperate with specific mutant Ras family member(s). We discovered that while Myc selects for the outgrowth of Nrasmut and Krasmut tumors, PIK3CAH1047R only selects for the outgrowth of Krasmut tumors. Based on our findings, we propose that cooperating oncogenes provide selective pressure for genetically distinct Ras-initiated premalignant clones. In a second set of experiments, we evaluated how parity impacts the progression of premalignant clones. We first tested whether parity blocks tumorigenesis by modifying our first set of experiments to include one or two rounds of parity after DMBA initiation and before inducing the expression of an oncogenic transgene. Despite the known protective effects of pregnancy against breast cancer, our parity protocols did not block tumorigenesis, regardless of cooperating oncogene (Myc vs. PIK3CAH1047R) and the number (one vs. two) and timing (peri-pubertal vs. adulthood) of pregnancies. However, parity did impact which clones progressed to malignancy. In both Myc- and PIK3CAH1047R-expressing models, the prevalence of Krasmut tumors was decreased in the context of parity, which implies that parity exerted selective pressure against the progression of Krasmut clones. Moreover, this selective pressure appears stronger as the number of pregnancies increases regardless of the cooperating oncogene and timing of pregnancy, as demonstrated by the decreased prevalence of Krasmut tumors. Lastly, pubertal parity revealed a slightly stronger selection against the Krasmut premalignant clone in PIK3CAH1047R-expressing models compared to adult parity. Thus, parity can exert contextual selection against specific Ras-initiated premalignant clones. In a third and final set of experiments aimed at targeting "undruggable" Myc-driven tumorigenesis, we discovered that Myc selects for a threshold level of PI3K signaling activation. While previous studies show that Myc cooperates with oncogenic Ras, targeted therapies against Ras remain limited to G12C Kras mutants, which is rare in human breast cancer. Hypothesizing that Myc/Ras cooperation involves the activation of a specific downstream Ras effector pathway, namely the phosphoinositide 3-kinase (PI3K) pathway, we generated a mouse model that expresses both iPIK transgene and constitutive, mammary-specific Myc transgene (cMyc). By inducing various levels of PIK3CAH1047R expression, we demonstrated that Myc requires a minimum level of PI3K pathway activation to generate mammary tumors reliably with decreased latency and increased multiplicity. These tumors also lack stereotypical Ras mutations, which implies that PI3K pathway activation relieved the selective pressure to select for Rasmut Myc-driven tumors. In addition, PIK3CAH1047R expression was reactivated by gene-switch mutations in Myc-expressing relapse tumors, further reinforcing a strong selective pressure for PI3K pathway activation.

Download or read book Comparative Oncology written by Alecsandru Ioan Baba and published by . This book was released on 2007 with total page 787 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Quest for the Cure written by George R. Blumenschein and published by Academic Press. This book was released on 2013-10-16 with total page 108 pages. Available in PDF, EPUB and Kindle. Book excerpt: This original fourteen chapter book is a brief, slightly autobiographic tale of medical oncologists, surgeons, radiation oncologists, and breast cancer patients in a well-established cancer center in Texas, who pursued the goal of cure for breast cancer. The evolution of improved outcomes in the treatment of microscopic metastatic breast cancer is also the story of the development of adjuvant chemotherapy for post-operative breast disease. The adjuvant therapy of breast cancer came about with the realization that this malignancy, when diagnosed in most patients, had spread beyond the confines of the primary cancer. Patient histories in the form of Case Studies are used to illustrate certain issues Devoted to the development of the chemotherapeutic regimens that currently are used to treat patients with advanced breast cancer

Download or read book Targeted Therapies in Breast Cancer written by Gw Sledge and published by Clinical Pub. This book was released on 2012-06 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: This new volume updates the reader on selected areas of targeted therapy in breast cancer, with special emphasis on chemoprevention strategies, drug resistance, biomarkers, combination chemotherapy, angiogenesis inhibition and pharmacogenomics in the context of clinical efficacy. This selected review of targeted therapies will guide the reader on effective treatment as part of an integrated programme of patient management.

Download or read book Elucidating Evolutionary Constraints of Mouse Mammary Cancer Using Adenomatous Polyposis Coli Mutations written by Ross Keller and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is a disease of evolution. Species evolve because mutations are passed to progeny through the germline, but somatic cells acquire mutations as well, and somatic mutation can initiate cancer. In addition, established cancers themselves evolve. Within a tumor, ongoing mutagenesis creates cell-to-cell genetic diversity, allowing subpopulations to undergo natural selection in Darwinian fashion. With a surplus of cells and a staggering number of potential mutations, evolution could, in theory, empower a tumor to overcome a plethora of obstacles. But fortunately, cancer evolution is restricted. Chemical, genetic, cellular, and environmental evolutionary constraints make cancer vulnerable. To uncover novel constraints, we utilized mouse model systems of breast cancer, specifically models driven by mutations in the adenomatous polyposis coli (Apc) gene, which antagonizes oncogenic Wnt signaling.In Chapter 2, we show that chemical and genetic constraints can direct which oncogenes are selected to cooperate in driving cancer. In mice that develop reversible, Wnt pathway-dependent mammary cancers (iWnt mice), exposure to chemical carcinogens that preferentially form adducts with either adenine (7,12 dimethylbenz(a)anthracene, DMBA) or thymine (N-ethyl-N-nitrosourea, ENU) resulted in activating mutations affecting different genes in the oncogenic Ras-Raf pathway (HrasCAA61CTA or BrafGTG636GAG, respectively). Both these mutations occur at A:T base pairs, but differ because in Hras, adenine resides on the sense strand, while in Braf, thymine does. This implicated strand-biased processes, such as strand-specific DNA repair, in mutagenesis. To confirm this, we generated DMBA- and ENU-induced mammary tumors in Apcmin mice, which inherit one nonfunctional Apc allele but routinely acquire second-hit mutations en route to mammary tumorigenesis. Exposure to each chemical led to distinct second-hit Apc mutation patterns, including strand-inverse mutation signatures at A:T sites, which precisely matched the mutation bias observed in Ras-Raf oncogenes. The findings indicate that a mutagens chemistry paired with DNA repair processes may have an outsized influence on which cancer driver genes are selected, independent of other pressures.In Chapter 3, we exploited patterns of second-hit Apc driver mutations to demonstrate that ionizing radiation (IR) perturbs mutation spectra in a dose-dependent manner, implying different doses drive cancer evolution via different mechanisms. In Apcmin mice, low-dose IR exposure (1 Gy), whether administered as a one-time dose or fractionated daily doses increased mammary tumor incidence without altering the mutation spectrum compared with IR-nave tumors. By contrast, high-dose IR (5 Gy) not only increased tumor incidence, but also shifted the mutation spectrum towards microdeletions, a putative signature of DNA double strand break (DSB) repair. Since IR is routinely used to treat breast cancer patients, we went on to determine how IR exposures impact mammary tumor cells. We introduced the Apcmin allele into iWnt mice and determined how IR exposure delivered prior to Wnt withdrawal impacted second-hit Apc mutations responsible for initiating relapse. Again, effects of low- and high-dose IR diverged. Low-dose IR augmented relapse but did not change the mutation spectrum from IR-nave. By contrast, high-dose IR augmented relapse further and exhibited a microdeletion signature characteristic of DSBs. Thus, high IR doses likely introduce DNA mutations by direct DNA damage, while lower doses promote tumor evolution via indirect mechanisms. These findings have implications for assessing cancer risk and planning radiotherapy regimens.Finally, in Chapter 4 we establish that oncogene overdose is a powerful evolutionary constraint that remains in force throughout tumor lifespan. At tumor initiation, mammary gland cells acquired mutations conferring an elevated, but submaximal oncogenic signal, avoiding oncogene overdose. However, for overdose to render cancer vulnerable, the constraint must remain through stages of tumor progression. Thus, we show that tumor cells responsible for initiating relapse following Wnt withdrawal (i.e. rescue subclones, RSCs) acquired second-hit Apc mutations conferring oncogene overdose avoidance, but we also show RSCs are still susceptible to oncogene overdose. Selection for these mutations during therapy involves an evolutionary trade-off. Rescue mutations, which enhance fitness by restoring oncogenic signaling during therapy, instead reduce fitness by driving oncogene overdose while superimposed on native (i.e., undrugged) signaling. Consistent with this model, RSCs underwent dynamic turnover prior to therapy, and RSCs generated by a timed mutagen exposure decreased in number when therapy was delayed or transiently interrupted. We ruled out neutral drift dynamics by demonstrating RSCs compete poorly against therapy-sensitive parental clones during tumor growth and were lost when the endogenous signal is increased to maximum. Exploiting this vulnerability could further efforts to eliminate cancer cells that drive relapse.

Download or read book The Evolution of Me written by Anastasia R. Stevenson and published by Christian Faith Publishing, Inc.. This book was released on 2021-07-30 with total page 159 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book is an all-in detailed journey through one of life's most challenging battles. In it, Anastasia provides excellent insight into her journey with breast cancer. She provides helpful hints on how to thrive through the journey, leaning entirely on her faith and her family. Anastasia details the ups and downs through being diagnosed at age thirty-four, a wife and mom to three little ones. Anastasia holds nothing back as she dives into motherhood, friendship, and marriage. With the God-given strength she was given, she shares all of the changes and challenges the cancer journey brings. I didn't choose cancer. It chose me, but I did decide what I would do with it. I would lend my voice to the situation. I would encourage, empower, and give hope. I would shine in times of darkness, and I would get up after every fall. - Anastasia Stevenson

Download or read book The Evolution of Mammary Cancer Induced in Virgin Female IF Mice with Minimal Doses of Locally acting Methylcholanthrene written by Georgiana M. Bonser and published by . This book was released on 1954 with total page 16 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Ecology and Evolution of Cancer written by Beata Ujvari and published by Academic Press. This book was released on 2017-02-08 with total page 292 pages. Available in PDF, EPUB and Kindle. Book excerpt: Ecology and Evolution of Cancer is a timely work outlining ideas that not only represent a substantial and original contribution to the fields of evolution, ecology, and cancer, but also goes beyond by connecting the interfaces of these disciplines. This work engages the expertise of a multidisciplinary research team to collate and review the latest knowledge and developments in this exciting research field. The evolutionary perspective of cancer has gained significant international recognition and interest, which is fully understandable given that somatic cellular selection and evolution are elegant explanations for carcinogenesis. Cancer is now generally accepted to be an evolutionary and ecological process with complex interactions between tumor cells and their environment sharing many similarities with organismal evolution. As a critical contribution to this field of research the book is important and relevant for the applications of evolutionary biology to understand the origin of cancers, to control neoplastic progression, and to prevent therapeutic failures. Covers all aspects of the evolution of cancer, appealing to researchers seeking to understand its origins and effects of treatments on its progression, as well as to lecturers in evolutionary medicine Functions as both an introduction to cancer and evolution and a review of the current research on this burgeoning, exciting field, presented by an international group of leading editors and contributors Improves understanding of the origin and the evolution of cancer, aiding efforts to determine how this disease interferes with biotic interactions that govern ecosystems Highlights research that intends to apply evolutionary principles to help predict emergence and metastatic progression with the aim of improving therapies

Download or read book Cancer Evolution written by Charles Swanton and published by Perspectives Cshl. This book was released on 2017 with total page 350 pages. Available in PDF, EPUB and Kindle. Book excerpt: Tumor progression is driven by mutations that confer growth advantages to different subpopulations of cancer cells. As a tumor grows, these subpopulations expand, accumulate new mutations, and are subjected to selective pressures from the environment, including anticancer interventions. This process, termed clonal evolution, can lead to the emergence of therapy-resistant tumors and poses a major challenge for cancer eradication efforts. Written and edited by experts in the field, this collection from Cold Spring Harbor Perspectives in Medicine examines cancer progression as an evolutionary process and explores how this way of looking at cancer may lead to more effective strategies for managing and treating it. The contributors review efforts to characterize the subclonal architecture and dynamics of tumors, understand the roles of chromosomal instability, driver mutations, and mutation order, and determine how cancer cells respond to selective pressures imposed by anticancer agents, immune cells, and other components of the tumor microenvironment. They compare cancer evolution to organismal evolution and describe how ecological theories and mathematical models are being used to understand the complex dynamics between a tumor and its microenvironment during cancer progression. The authors also discuss improved methods to monitor tumor evolution (e.g., liquid biopsies) and the development of more effective strategies for managing and treating cancers (e.g., immunotherapies). This volume will therefore serve as a vital reference for all cancer biologists as well as anyone seeking to improve clinical outcomes for patients with cancer.

Download or read book A Microscopical Study of the Evolution of Mouse Mammary Cancer written by Georgiana M. Bonser and published by . This book was released on 1945 with total page 10 pages. Available in PDF, EPUB and Kindle. Book excerpt:

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 Cancer through the Lens of Evolution and Ecology written by Jason A. Somarelli and published by CRC Press. This book was released on 2024-05-29 with total page 306 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer cells exist in an ever-changing “ecology” and are subject to evolutionary pressures just like any species in nature. This edited book explores the following themes: 1) how the dynamics of mutation, epigenetics, and gene expression noise are sources of genetic diversity; 2) how scarce resources influence cancer therapy resistance; 3) how predator-prey dynamics are mirrored in immune-cancer cross-talk; 4) how cancer cells parallel niche construction theory; 5) how changing fitness landscapes enable cancer growth; and 6) how cancer cells interact within the body. The book is a resource for understanding cancer as a disease of multicellularity grounded in evolutionary principles. By using this knowledge, researchers are starting to exploit these behaviors for treatment paradigms. Key Features Bridges disciplines exemplifying the ways disparate fields create new perspectives when integrated. Offers insights from leading scholars in cancer biology, ecology and evolutionary biology. Provides a timely recognition by oncologists that evolutionary paradigms are crucial for breakthroughs in cancer treatment. Integrates basic and applied sciences of oncology and evolutionary biology.

Download or read book Breast Cancer written by John G. Gruhn and published by . This book was released on 1994 with total page 82 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Frontiers in Cancer Research written by Carlo C. Maley and published by Springer. This book was released on 2016-11-21 with total page 266 pages. Available in PDF, EPUB and Kindle. Book excerpt: This is the ideal book for anyone contemplating starting a career in, or shifting their career to, studying the dynamics that drive cancer progression and its response to therapy. Topics include the theory and population genetics of cancers, genetic diversity within tumors (intra-tumor heterogeneity), understanding how mutant clones expand in tissues, the role of cancer stem cells in the dynamics of tumors, the evolution of metastasis, and how to improve cancer therapy by addressing the evolution of cancers in response to our interventions. There are also chapters on the patterns of cancer susceptibility in humans due to a mismatch between our modern environment and the environment in which our ancestors evolved, as well as a chapter on the evolution of cancer suppression mechanisms that have evolved in different species, particularly the large long-lived animals like elephants and whales that are better at suppressing cancers than humans. This book serves as a primer on the evolutionary and ecological theory of cancer- the framework upon which all the details of cancer may be hung. It is ideal for oncologists and cancer researchers interested in evolutionary theory, and evolutionary biologists and ecologists interested in gaining insights into cancer development and prevention.

Download or read book Genetic and Phenotypic Evolution of Breast Cancer written by Tuula Kuukasjärvi and published by . This book was released on 1997 with total page 59 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Evolution of Cancer written by Shinichi Okuyama and published by . This book was released on 1990 with total page 290 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Evolutionary Biology of Tumor Initiation and Progression written by Yusuke Suenaga and published by Frontiers Media SA. This book was released on 2024-06-28 with total page 151 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cancer is characterized by heterogeneous cells with capacity for self renewal, and selective pressures in the microenvironment which constantly change the cell population. This "descent with modification" is consistent with Darwin's definition of evolution, and accordingly, cancer progression can be captured from an evolutionary angle. However, there is also a clear difference between cancer progression and biological evolution. First, contrary to the evolution of complex organisms, cancer originates from cells of multicellular organisms that escape their constraints and behave like unicellular organisms. Therefore, from the beginning, cancer cells have complex genomes that contain abundant genetic materials which they can use to change their phenotype by dynamic rearrangements and modifications. Secondly, epigenetic effects promote cancer evolution in contrast to the evolution of life. Some tumors develop with minimal genetic alterations, and cell plasticity contributes to both initiation and progression in various tumors. However, an evolutionary theory that encompasses these characteristics of cancer remains to be developed.