2 edition of role of TIMP3 in mammary gland morphogenesis, involution, inflammation, and tumourigenesis. found in the catalog.
role of TIMP3 in mammary gland morphogenesis, involution, inflammation, and tumourigenesis.
Carlo Vincent Hojilla
Written in English
Responsible for producing milk that protects and nourishes the offspring, the mammary gland undergoes cyclical remodeling as dictated by estrous and gestation. The orchestration of mammary gland cell types with local and systemic tissue microenvironment factors can create an epithelial arbor, or differentiate it to secretory units, or even deconstruct the tissue. Ironically, the same remodeling property of the gland renders it susceptible to lesions, including breast cancer.Given the pro-apoptosic and pro-inflammatory roles of TIMP3 loss in involution, its role in mammary tumourigenesis was next investigated. Loss of TIMP3 caused a greater than 90% reduction in tumour burden and metastasis in MMTV-PyMT , an aggressive model of breast cancer. In the non-viral oncogenesis, physiological model, MMTV-Neu, 40% of Timp3 -/- mice were resistant to mammary tumours. Tumours that did emerge in Timp3-/- mice were more malignant. In both models, Timp3 heterozigosity inhibited tumourigenesis. Further, Timp3-null stroma halted the growth of initiated tumours and mammary epithelial cells derived from Timp3-/- tumours were more sensitive to apoptosis compared to controls. Tumourigenesis attenuation was accompanied by increased infiltration of macrophages, CD4+, and CD8+ T-cells. These studies demonstrate the critical role of TIMP3 during mammary gland physiology and tumourigenesis. Importantly, the loss of one or both Timp3 alleles results in mammary tumour suppression, providing an impetus for exploring TIMP3 as a potential therapeutic target against breast cancer.Extracellular proteolysis mediated by the balanced activity of matrix metalloproteinase (MMP) and tissue inhibitors of metalloproteinases (TIMPs) facilitates mammary gland remodeling. In particular, TIMP3 has the capacity to not only control ECM protein turnover, but also regulate the shedding and bioactivity of ligands and cell surface molecules. The role of TIMP3 in signaling mechanisms governing mammary gland biology were investigated using genetically engineered mice. Timp3-/- primary mammary epithelial cells had increased transcriptional activity of the survival factor, beta-catenin, consistent with an acceleration of epithelial ductal morphogenesis. During post-lactational mammary gland involution, TIMP3 deficiency caused accelerated mammary epithelial apoptosis through a concerted fragmentation of E-cadherin and activation of TNF-dependent apoptosis. Concomitantly, an increased infiltration of macrophages and sustained T-cell presence were observed, which were not mitigated in Timp3-/-/Tnf-/- mice.
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Three-dimensional (3D) mammary organoid culture has become an important tool in mammary gland biology and enabled invaluable discoveries on pubertal mammary branching morphogenesis and breast . The estrogen and insulin-like growth factor (IGF-I) axes occupy central roles in normal mammary gland development and breast cancer. β estradiol (E2) and IGF-I synergize to regulate formation of terminal end buds and ductal elongation during pubertal by: 4.
Obesity and low-grade inflammation are associated with an increased risk of hepatocellular carcinoma (HCC), a leading cause of cancer-related death worldwide. The tissue inhibitor of metalloproteinase (TIMP) 3, an endogenous inhibitor of protease activity that represents a key mediator of inflammation, is reduced in inflammatory metabolic disorders and cancer. In contrast, Timp3 Author: Viviana Casagrande, Viviana Casagrande, Alessandro Mauriello, Lucia Anemona, Maria Mavilio, Giulia I. To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of Cited by: 9.
To our knowledge, this study is the first to demonstrate that an inhibitor of an extracellular proteinase is necessary for maintaining the conserved processes of mammary gland involution and function. Moreover, deficiencies in TIMP-3 function led to excessive and unscheduled physiological apoptosis in mammary by: Two rapidly evolving fields are converging to impact breast cancer: one has identified novel substrates of metalloproteinases that alter immune cell function, and the other has revealed a role for inflammation in human cancers. Evidence now shows that the mechanisms underlying these two fields interact in the context of breast cancer, providing new opportunities to understand this disease Cited by:
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The role of TNF in mammary involution of the Timp3 deficient gland TIMP3 regulates the bioactivity of the inflammatory cytokine TNF since it is the physiological inhibitor of the TNF sheddase by: TIMP3, an inhibitor of MMP2, appears to be particularly important as involution is accelerated in TIMP3-deficient mammary glands and first phase reversibility is lost.
Concomitant with the loss of the mammary epithelium through apoptosis, the surrounding adipocytes differentiate, a process requiring both plasmin and MMP3 and tumourigenesis.
book 5, 29 ].Cited by: While the classic function for TIMPs is inhibition of metalloproteinase activity, both TIMP2 and -3 involution also been found to inhibit VEGF signaling through metalloproteinase-independent mechanisms. 46, For TIMP3, this inhibition occurs through TIMP3 binding to the VEGF receptor and blocking VEGF–VEGFR2 interaction, ultimately inhibiting.
Induction of synchronized involution and collection of mammary tissue. In both experimental (Timp-3 –/–) and control groups (wild-type), litter size was kept at six pups to maintain even suckling frequency on each teat and minimize intermouse mammary gland synchronize involution, litters were removed from dams after by: Myogenic differentiation in adult muscle is normally suppressed and can be activated by myogenic cues in a subset of activated satellite cells.
The switch mechanism that turns myogenesis on and off is not defined. In the present study, we demonstrate that tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of TNFα-converting enzyme (TACE), acts as an on–off switch for Cited by: The tumor-suppressor role of TIMP3 is also documented by a large 3-deficient mammary gland.
invasion and in vivo tumorigenicity of thyroid tumor cells Cited by: STAT3 was first described as an acute phase response regulator in the liver, where its transcriptional activity was activated by phosphorylation of a single tyrosine residue [1,2].In the subsequent two decades, a plethora of studies has delineated the initially surprising, and key, role of this transcription factor as a mediator of mammary gland postlactational regression (involution) (), and Cited by: Increased and sustained inflammatory and immune response in Timp3 2/2 involuting glands.
(A) Representative images of F4/positive cells during wild-type (WT) and Timp3 2/2 involution. In addition to embryo implantation, TIMP3 acts as a major facilitator of extracellular matrix sparing in several other homeostatic processes, including lung and bone development and remodeling as well as mammary gland involution.
In mice lacking TIMP3 (Timp3 −/− mice), metalloproteinase activity is increased in the lungs during development Cited by: Mesenchyme- dependent morphogenesis and epithelium-specific cytodifferentia- tion in mouse mammary gland. ScienceORMEROD AND RUDLAND Mammary Gland Morphogenesis in Vitro TURNER, C.
W., and GOMEZ, E. The normal development of the mammary gland of the male and female albino mouse. Agric. Exp. Station Res. BuH Cited by: Adissu, H. et al. Timp3 loss accelerates tumour invasion and increases prostate inflammation in a mouse model of prostate cancer. Prost – (). CASCited by: Induction of synchronized involution and collection of mammary tissue.
In both experimental (Timp-3 –/–) and control groups (wild-type), litter size was kept at six pups to maintain even suckling frequency on each teat and minimize intermouse mammary gland synchronize involution, litters were removed from dams after 10L.
In mice, the lack of secreted frizzled-related protein 1 (SFRP1) is responsible for mammogenesis and hyperplasia, while, in bovines, its overexpression is associated with post-lactational mammary gland involution.
Interestingly, there are no reports dealing with the role of SFRP1 in female involution. However, SFRP1 dysregulation is largely associated with human tumorigenesis in the : Alisson Clemenceau, Caroline Diorio, Francine Durocher. We review literature on mammary gland physiology, murine mammary tumor models and clinical breast cancer studies, in each case summarizing what is known regarding the metalloproteinase axis as well as seeking evidence for its role as a mediator of by: PDF | Background Macrophages play diverse roles in mammary gland development and breast cancer.
CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine | Find, read and cite all the research. Age is the primary risk factor for breast cancer in women. Bipotent basal stem cells actively maintain the adult mammary ductal tree, but with age Cited by: Ensembl ENSG ENSMUSG UniProt P P RefSeq (mRNA) NM_ NM_ RefSeq (protein) NP_ NP_ Location (UCSC) Chr – Mb Chr – Mb PubMed search Wikidata View/Edit Human View/Edit Mouse Metalloproteinase inhibitor 3 is a protein that in humans is encoded by the TIMP3 gene.
This gene Aliases: TIMP3, HSMRK, K, KTA2. During mammary gland involution, a local inflammatory response occurs in the absence of infection (25, 37). Lcn2 is an acute phase protein (APP) with high expression in the mammary gland and.
C.J. Sympson, R.S. Talhouk, C.M. Alexander, J.R. Chin, S.M. Clift, M.J. Bissell, Z. WerbTargeted expression of stromelysin-1 in mammary gland provides evidence for a role of proteinases in branching morphogenesis and the requirement for an intact basement Cited by: Mammary gland development.
At the onset of puberty, the rudimentary ductal tree present at birth (Hogg et al. ) undergoes a dramatic expansion to fill the surrounding fat rodents, terminal end buds residing at the ends of primary ducts and comprised of an outer layer of cap cells and a multilayered core of body cells rapidly penetrate the surrounding fat pad, periodically Cited by:.
Studies of postpartum mammary gland involution reveal novel pro-metastatic have been extensivel y studied for their role in breast tumor.
as TIMP3 has been implicated in the.The embryonic mammary organ is referred to as the mammary primordium (MP) (Fig. 1A–C).In the Estage mouse embryo, the MP is comprised of a multilayered lens-shaped epithelium with non-descript mesenchyme underlying it.By Estage, several layers of dermal mesenchyme adjacent to the mammary bud epithelium have condensed and aligned into a concentric by: Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3.
Breast Cancer Res. ; 6:R75–R doi: /bcr [PMC free article] Monks J, Geske FJ, Lehman L, Fadok VA. Do inflammatory cells participate in mammary gland involution?Cited by: