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Understanding the Early Events in Breast Carcinogenesis by Inactivating p16INK4a in Primary Human Mammary Epithelial Cells
Get PDFCancer cells arise from normal cells that have acquired the ability to expand beyond the constraints of a tissue microenvironment. Normal human cells have many mechanisms to prevent carcinogenesis. During the process of carcinogenesis one of the properties a cell must acquire is the ability to evade anti-proliferative signals. Many stimuli cause normal cells to activate a cell cycle arrest. The p16INK4a gene is an important tumor suppressor that activates a cell cycle arrest in response to stimuli like stress, DNA damage, and senescence. Inactivation of p16INK4a occurs in many tumor types and allows the cells to bypass many anti-proliferative signals. Inactivation of p16INK4a is found in about 30% of breast tumors (Rocco and Sidransky, 2001), yet the consequences of that inactivation are not completely understood. We sought to improve our understanding of p16INK4a inactivation in breast carcinogenesis by inactivating p16INK4a in primary human mammary epithelial cells (HMEC). Studying primary human cells allowed us to understand the consequences of p16INK4a inactivation in cells with a wild-type genetic background. Additionally, this system allowed us to examine the role of p16INK4a in early breast carcinogenesis, with a long-term goal of identifying avenues for early detection and preventive intervention of breast cancer. In Chapter II, we describe how inactivation of p16INK4a modulates the levels and functions of another important tumor suppressor gene, p53. The Rb pathway is identified as being necessary for p16INK4a to modulate p53. In Chapter III, we further our understanding of the modulation of p53 by p16INK4a and determine that ATM and the DNA damage response may be involved. Regulation of cell cycle checkpoints following p16 inactivation is also examined. In Chapter IV, we perform global gene expression analysis to identify new genes and pathways modulated by inactivation of p16INK4a in HMEC. We identify chitinase-3-like-1 as a novel p16INK4a regulated gene that is overexpressed in the basal-like subtype of invasive breast tumors. Chitinase-3-like-1 may be useful as a serum biomarker or therapeutic target for basal-like breast tumors
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Aerobic Glycolysis: A Novel Signature of Premalignancy in Disease-free Breast Tissue
Get PDFIt is well established that tumors exhibit abnormal aerobic glycolysis, a metabolic alteration known as "Warburg effect". However, it is unclear whether this phenotype reflects a metabolic shift during carcinogenesis or alternatively is a pre-existing event. In the present dissertation, we establish that a variant subpopulation of primary, non-transformed human mammary epithelial cells (vHMEC) shares this aerobic glycolysis signature with cancer cell lines. This phenotype is characterized by an increase in lactate production and synthesis as a result of lactate dehydrogenase (LDH) upregulation and is modulated by both hypoxia-induced factor HIF-1α and AKT. Strikingly, simultaneous over-expression of COX-2 and LDHA can be detected in morphologically normal epithelial cells in disease-free breast tissue, supporting that aerobic glycolysis pre-exists in vivo prior to carcinogenesis. Furthermore, we demonstrate that the lactate accumulation occurring in vHMEC can be readily detected by magnetic resonance spectroscopy (MRS), suggesting that aerobic glycolysis can be monitored in vivo. These novel findings further our understanding of pre-malignant events and could potentially lead to dramatic improvements in non-invasive detection of premalignant lesions in breast cancer patients
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Tissue States Provide Novel Insights into Attributes that Drive Metastasis
Get PDFRecently, in Nature Medicine, Schedin and colleagues define attributes within the involuting postpartum breast microenvironment that promote breast cancer metastasis. Cell invasiveness is controlled by a positive feedback loop involving COX-2 and fibrillar collagen. NSAIDs suppress tumor progression during postpartum involution, potentially providing effective agents for intervention in pregnant women
Reflections on miR-ing Effects in Metastasis
Get PDFIn a recent issue of Cell, Valastyan et al. demonstrate that miR-31 can regulate multiple steps in the metastatic cascade independent of confounding effects on primary tumor development. These data have potential to provide biomarkers for prognosis and novel targets for intervention in this most lethal aspect of malignancy
A Twist of Cell Fate
Get PDFIndividuals carrying deleterious BRCA1 mutations typically develop basal-like rather than luminal breast cancers. In this issue of Cell Stem Cell, Proia et al. (2011) study breast tissue from women with heterozygous BRCA1 mutations and identify molecular mechanisms that regulate mammary progenitor cell differentiation and bias toward subsequent basal-like tumor formation
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