1,721,087 research outputs found
Recommended from our members
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
Recommended from our members
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
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
Functions of p53 suppress critical consequences of damage and repair in the initiation of cancer
Get PDFAbstractA pivotal study reveals a long-sought-after mechanism for gene amplification and provides important implications for oncogenesis
Recommended from our members
Stromal cells can contribute oncogenic signals
Get PDFThe majority of studies of neoplastic transformation have focused attention on events that occur within transformed cells. These cell autonomous events result in the disruption of molecular pathways that regulate basic activities of the cells such as proliferation, death, movement and genomic integrity. Other studies have addressed the microenvironment of tumor cells and documented its importance in supporting tumor progression. Recent work has begun to expand on these initial studies of tumor microenvironment and now provide novel insights into the possible initiation and progression of malignant cells. This review will address the transforming effect of stromal cells on epithelial components
Recommended from our members
Cell-adhesion-dependent influences on genomic instability and carcinogenesis
Get PDFAdhesion-dependent cell signaling is known to be important in carcinogenesis. It is postulated that several types of adhesion molecules act as tumor suppressor genes by enforcing cell-substrate and cell-cell adhesion thereby preventing the migration of cells and their invasion into surrounding tissues. Recent evidence, however, suggests that disruption of adhesion systems can both initiate neoplastic transformation and contribute a rate-limiting step to progression. Adhesion may modulate neoplastic processes by altering pathways that control genomic stability. Analysis of the adhesion-controlled inactivation of the p53 protein and the concomitant relaxation of cell cycle checkpoint control could identify the critical contributions of adhesion-mediated influences to carcinogenesis
Recommended from our members
Extended abstract: Abrogation of cell cycle checkpoint control in preneoplastic cells
Get PDFAbstract Genomic integrity is maintained by a network of cellular activities that assesses the status of the genome at a given point in time and that provides signals to proceed with or to halt cell cycle progression. Recent studies have identified cellular proteins that are the targets for the viral oncoproteins involved in these processes. We demonstrate that the expression of human papilloma virus type 16 E6 and E7 oncoproteins in normal mortal cells disrupts the integration of the network of signals that maintain genomic integrity. © 1995 Wiley‐Liss, Inc
- …
