The Role of Stroma in WNT-induced Mammary Gland Development and Tumorigenesis PDF Download
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Author: Young Chul Kim
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ISBN:
Category :
Languages : en
Pages : 154
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Author: Young Chul Kim
Publisher:
ISBN:
Category :
Languages : en
Pages : 154
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Author: Bob Y. Liu
Publisher:
ISBN:
Category :
Languages : en
Pages : 164
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Author: Anisha Mathur Hammer
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ISBN:
Category : Carcinogenesis
Languages : en
Pages :
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Breast cancer remains the leading cause of cancer-related mortality in women worldwide. One of the many confounding factors in the treatment of this malignancy is the cellular heterogeneity of the breast. The normal breast is comprised of epithelial ducts, which are surrounded by a layer of basement membrane that separates the stroma from the ducts. The stroma itself is composed of yet other cell types- adipocytes, fibroblasts, immune cells, endothelial cells that make up blood vessels and pericytes that hug the endothelial cells. In the past decade, the tumor microenvironment, the stroma of the tumor, has emerged as a hallmark of cancer. Different components of this “microenvironment” become activated and fuel tumor progression to give rise to more aggressive, metastatic disease. While earlier diagnoses and development of targeted therapies have improved patient outcomes, this heterogeneity is still a cause for therapeutic resistance and metastatic spread, both of which encumber treatment and challenge patient survival. In this study, we report on the roles of Platelet-Derived Growth Factor Receptors (PDGFRs) alpha and beta in mammary carcinoma. PDGFRs are receptor tyrosine kinases, which upon ligand binding initiate a signaling cascade that results in major cellular processes such as proliferation and migration. They act in an oncogenic capacity in certain types of cancers of the lung, brain and blood. In an autocrine capacity, i.e. signaling within the tumor cells, their oncogenic role in breast cancer was reported, however their role in the stroma of breast cancer remains understudied. The central goal of this study thus was to elucidate the roles of PDGFRa and PDGFRß signaling in the mammary gland microenvironment, in both development and carcinogenesis. To address this question, genetic mouse models of stroma-specific activation of either PDGFRa or PDGFRß were utilized. We have found that while activation of PDGFRa abrogated mammary gland development, PDGFRß activation in the stroma caused an increase in tertiary side-branching. We found that PDGFRa activation led to progressive fibrosis in the mammary fat pad, resulting in altered matrix mechanics. These changes likely led to the increased orthotopic tumor growth observed. Primary tumor growth was also accelerated in the PDGFRß mutants, when PDGF-BB expressing cells were injected into mammary glands of these mice. Further, when the same tumor cells were intravenously injected, PDGFRß mutants preferentially had breast brain metastases, but metastases to the lung, liver and spine were unchanged between the mutant and control animals. Furthermore, when these tumor cells were injected intracranially (in the brain), tumors grew faster in the PDGFRß mutant compared to controls. Importantly, PDGFB expression predicted metastases free and overall survival in breast cancer patient data sets. Combined our results reveal novel non-cell autonomous roles of stromal PDGFRs in creating a tumor supportive environment.
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Category :
Languages : en
Pages : 0
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The purpose of this grant is to define interactions between stroma and epithelium in mammary oncogenesis in mice transgenic for Shope growth factor (SGF). Different lines of SGF transgenic mice express this EGF-like cytokine using inducible (metallothionein, MT) or constitutive (RSV-LTR) promoters. For the year now ending, most stated goals have been met, although some remain. We made sufficient SGF-transgenic mice of RSV-SGF and MT-SGF lines to analyze mammary differentiation and oncogenesis, including testing SGF expression and that of particular cellular genes that are important in these processes. It also induced defining which cells express the transgene and these cellular genes. We have also interbred RSV- and MT-SGF transgenic mice with p53-/- mice, to determine the nature of the interactions between homozygous deletion of p53 tumor suppressor gene and SGF expression as regards mammary gland development and tumorigenesis. These mice have been analyzed, and additional numbers of them are being produced. Our study of SGF activity in cultured cells has been progressing more slowly, and these studies are largely still in progress. Thus, our studies of the effects of SGF on the murine mammary gland are proceeding, and additional work is in progress.
Author: Tze Peng Lim
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ISBN:
Category : Dissertations, Academic
Languages : en
Pages : 286
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Author: Bert W. O'Malley
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ISBN:
Category : Cyclic nucleotides
Languages : en
Pages : 488
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Hormone assays; Hormone receptors; Evaluation of biological effects of hormones; Purification and synthesis of hormones.
Author: Bryony Wiseman
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ISBN:
Category :
Languages : en
Pages : 18
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The mammary gland relies on stromal-epithelial interactions for proper development. Tumorigenesis occurs when these signals are misinterpreted. Here we show that stromal matrix metalloproteinases (MMPs) have distinct roles in mammary gland branching morphogenesis. MMP activity is required for normal mammary gland development since mice treated with a synthetic MMP inhibitor, GM6OOl, have retarded ductal development. Furthermore, 3D cultures of mammary organoids also require MMP activity to branch in response to growth factors, indicating a mammary specific response. We also show that specific MMPs are required for distinct aspects of mammary gland morphogenesis. Specifically, MMF-3 is needed for branching because MMP-3 null mice have significantly fewer branches than controls. However, the ductal length is normal. In contrast, MMP-2 is required for ductal elongation, since the ducts of MMP-2 null mice are retarded in their penetration into the fat pad. However, the branching of the MMP-2 null ducts is normal. MMP-l4 is a known activator of MMP-2 and we show it is highly expressed in front of terminal end buds. Mammary glands deficient in MMP-l4 grown under the kidney capsule of nude mice also have defective ductal morphogenesis. Thus, these stromal enzymes are important, and have distinct roles, in patterning the mammary gland.
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Category :
Languages : en
Pages : 0
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We identified molecules that are involved in the cross talk between the epithelial and mesenchymal components of the developing and involuting mammary gland. The EFGR protein was shown to mediate normal ductal morphogenesis by acting from the stromal cells on the development of the mammary epithelial ducts. Additional evidence was provided concerning the function of the Caspase 1 gene product during lobular-alveolar development and involution of the mammary gland after weaning. An interesting observation from this work was mammary epithelial cells that will succumb to apoptosis enter the cell cycle first. This observation implies that at least a subset of the redundant epithelial cells undergo activation before cell death. In preliminary work mammary glands from the MMP14 null mouse were shown to have less adipose tissue but ductal penetration of the fat pad and initial duct formation occurred by post-natal day 13. Further experimentation is required to determine if the reduction in adipose tissue is related - to the wasting phenotype of these animals, or is induced by the MMP14 null epithelial cells. The practical outcome of these studies is a better understanding of mammary gland development before, during and after pregnancy, and during the process of involution.
Author: Maricel V. Maffini
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ISBN:
Category :
Languages : en
Pages : 20
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A complex network of signals between the stroma, the extracellular matrix and the epithelium, and by hormones acting systemically, drive the mammary gland development and function. The tissue organization field theory (TOFT) proposes that alterations of the reciprocal interactions between stroma and epithelium initiate the process of neoplastic transformation of epithelial cells. Our goal is to assess whether the primary target of the carcinogen N-nitroso-methylurea (NMU) is the epithelium, the stroma or both through a protocol of tissue recombination by transplanting mammary gland epithelial cells (MGEC) into mammary gland fat pads (MGFP) previously cleared of epithelium. The animals were divided into 6 groups: (1) NMu-exposed stroma and vehicle (VEH)-exposed MGEC; (2) NMU exposed stroma and NMU-exposed MGEC; (3) VEH-exposed stroma and NMU-exposed MGEC; (4) VEH- exposed stroma and VEH-exposed MGEC; (S) positive control (intact virgin rat exposed to NMU); (6) negative control (exposed to VEH). Results: the tumor incidence was Gl 83.3%, G2 85.7%, 03, 4 and 6 0%, OS 100%. Our results show that the stroma, rather than the epithelial cells, may be responsible for the development of a neoplasia. This novel concept in carcinogenesis will provide clues to be applied to more rational study of breast cancer.
Author:
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ISBN:
Category :
Languages : en
Pages : 46
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Both the growth and the development of the mammary gland are controlled by the female hormones estrogen and progesterone, and by interactions between the epithelial and stromal compartments of the breast. Changes in the regulation of any of these processes may lead to breast cancer. Therefore, we need to understand in detail the mechanisms that control proliferation and development of the mammary gland. We have investigated the role of progesterone in the process of sidebranching and alveologenesis In the mammary gland using mice laclting the progesterone receptor which are defective in these processes. By reconstituting murine mammary glands in vivo, we have shown that the progesterone receptor is required only in epithelial cells for proper sidebranching to occur. Our studies suggest that progesterone acts in a paracrine manner and more recent data suggests that Wnt-4 is a possible mediator of this paracrine effect. In parallel studies, we have observed that breast cancer cells can dramatically downregulate the expression of hepatocyte growth factor in cocultured libroblasts. These results suggest an important role of paracrine interactions also in breast cancer development. In addition, we have characterized the role of the estrogen receptor in regulating the proliferation of breast cancer cells. We postulate that the ability of estrogen receptor to control cyclin Dl expression and proliferation of breast cancer cells may be acquired during breast cancer development. In conclusion, we have studied the role of female hormones and stroma-epithelial interactions in regulating mammary gland development and tumorigenesis.
