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Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
This project addresses the question whether and, if so, how molecular lesions of the genes involved in the TGFB signaling pathway contribute to the origin and/or progression of breast cancer. We have cloned and determined the intron-exon structure of the TGFB type I receptor (TBR-I). This has allowed us to study this gene in a series of primary breast cancer specimens. Our most important finding is a much higher frequency of an exon 1 receptor variant among breast cancer cases than controls. Secondly, we have identified a serine to tyrosine mutation within the catalytic core of the TBR-I serine-threonine kinase domain in 2 of 31 primary and 5 of 12 metastatic breast cancer specimens. Thirdly, we have developed transient transfection as says to determine how specific TBR mutations affect receptor function. Using these assays we have shown that two previously identified TBR-II missense mutants are incapable of signaling because of the near complete loss of receptor kinase activity. Plans for the coming year include completing structural analyses of the TBR-I and -II genes in primary and metastatic breast cancer and defining the functional properties of the newly discovered TBR-I variant and mutant.
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
This project addresses the question whether and, if so, how molecular lesions of the genes involved in the TGFB signaling pathway contribute to the origin and/or progression of breast cancer. We have cloned and determined the intron-exon structure of the TGFB type I receptor (TBR-I). This has allowed us to study this gene in a series of primary breast cancer specimens. Our most important finding is a much higher frequency of an exon 1 receptor variant among breast cancer cases than controls. Secondly, we have identified a serine to tyrosine mutation within the catalytic core of the TBR-I serine-threonine kinase domain in 2 of 31 primary and 5 of 12 metastatic breast cancer specimens. Thirdly, we have developed transient transfection as says to determine how specific TBR mutations affect receptor function. Using these assays we have shown that two previously identified TBR-II missense mutants are incapable of signaling because of the near complete loss of receptor kinase activity. Plans for the coming year include completing structural analyses of the TBR-I and -II genes in primary and metastatic breast cancer and defining the functional properties of the newly discovered TBR-I variant and mutant.
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
This project addresses three fundamental research issues. The first question is whether or not molecular lesions of the genes involved in the TGFB signaling pathway contribute to the origin and/or progression of breast cancer. We expect changes in these genes to be relatively late events, perhaps characteristic of metastatic cancer. Secondly, we propose to determine how molecular lesions in the TGFB receptor and/or Smad genes affect receptor function, and how they might play a role in the development and/or progression of breast cancer. Thirdly, we intend to examine the question whether genetic lesions in TGFB receptor and/or Smad genes are able to predict the outcome of patients with breast cancer. Because the anti-tumor effects of anti-estrogens such as tamoxifen are thought to be mediated by the auto-and paracrine induction of TGFB, we wish to test the hypothesis that resistance of hormone-receptor positive cancers to tamoxifen is the result of inactivation of TGFB pathway genes.
Author: Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Transforming Growth Factor-Beta (TGF-Beta) is the most potent known inhibitor of cell cycle progression of normal mammary epithelial cells. In general, advanced breast cancers are refractory to TGF-Beta-mediated growth inhibition. The TGF-Beta type I and type II receptors (T-Beta-R-I and -II) are the primary transducers of TGF-Beta's antiproliferative effects. It is our working hypothesis that TGF-Beta-resistance is caused by lesions in the T-Beta-R genes. Using touch preps of primary breast carcinomas, we showed that approximately 50% of primary breast carcinomas contain subpopulations of cells that have lost one or both copies of the T-Beta-R-I or -II gene. Screening of the T-Beta-R-I and -II genes for the presence of mutations using PCR-SSCP and DNA sequencing indicate that a particular missense mutation (S387Y) in T-Beta-R-I is present in approximately 6% of primary cancers and 42% of axillary lymph node metastases. Finally, we have generated antibodies that specifically recognize the activated (phosphorylated) forms of Smad2 and -3. These allow us to assess in situ whether breast cancer cells are responding to TGF-Beta, and whether T-Beta-R defects are present or not. Approximately 12% of primary breast cancers fail to activate Smad2, indicating the presence of a TGF-Beta receptor defect.
Author: Sonia B. Jakowlew Publisher: Springer Science & Business Media ISBN: 1597452939 Category : Medical Languages : en Pages : 785
Book Description
Transforming Growth Factor- ß in Cancer Therapy, Vols. 1 and 2, provides a compendium of findings about the role of transforming growth factor- ß (TGF- ß) in cancer treatment and therapy. The second volume, Cancer Treatment in Therapy, is divided into three parts. The companion volume details the role of TGF- ß on basic and clinical biology.
Author: Sonia B. Jakowlew Publisher: Springer Science & Business Media ISBN: 1597452920 Category : Medical Languages : en Pages : 726
Book Description
Transforming Growth Factor- ß in Cancer Therapy, Vols. 1 and 2, provides a compendium of findings about the role of transforming growth factor- ß (TGF- ß) in cancer treatment and therapy. The first volume, Basic and Clinical Biology, is divided into three parts. This volume’s companion, Cancer Treatment in Therapy, examines transforming growth factor- ß in other developing and advanced cancers and methods of treatment and therapy.
Author: Publisher: ISBN: Category : Languages : en Pages : 26
Book Description
This combined final report for the research and career development grants relates to three objectives. Work on the first objective first focused on an analysis of the importance of TGF-beta expression as a determinant of clinical outcome. No such correlation was evident. Subsequent experiments examined the importance of a functionally intact TGF-beta signaling pathway with regards to tumor necrosis factor (TNF)-mediated cytotoxicity of MCF-7 cells, and documented that derepression of Bcl-2 expression as a consequence of loss of TGF-beta responsiveness likely underlies the acquired resistance to TNF. The second objective centered around an in vivo model of tumorigenicity and metastatic potential of breast cancer cells altered with regard to their production of and responsiveness to TGF-beta. Distinct paracrine and autocrine roles for TGF-beta were highlighted, with local invasiveness determined to be largely a paracrine effect of TGF-beta. The most rapid tumor growth was evident with the cells that remained responsive to TGF-beta however. The third onjective was to identify the molecular determinants of promoter usage for TCF-beta3 in breast cancer cell lines. Hypomethylation at a small grouping of CpGs in breast cancer cells was identified as a molecular correlate of downstream promoter activation.
Author: Marc E. Lippman Publisher: Springer Science & Business Media ISBN: 1461539404 Category : Medical Languages : en Pages : 455
Book Description
In Breast Cancer: Cellular and Molecular Biology [Kluwer Academic Pub lishers, 1988], we tried to present an introduction to the emerging basic studies on steroid receptors, oncogenes, and growth factors in the regulation of normal and malignant mammary epithelium. The response to this volume was superb, indicating a tremendous interest in basic growth regulatory mechanisms governing breast cancer and controlling its malignant progres sion. In the two years since its publication, much new and exciting in formation has been published and the full interplay of regulatory mechanisms is now beginning to emerge. We have divided this book into four sections that we hope will unify important concepts and help to crystallize areas of consensus and/or disagreement among a diverse group of basic and clinical scientists working on the disease. The first section is devoted to studies on oncogenes, antioncogenes, proliferation, and tumor prognosis. The first chapter, by Sunderland and McGuire, introduces the characteristics of breast cancer as studied by patho logists to establish prognostic outcome. Of particular interest is a new proto oncogene called HER-2 (or neu), which is rapidly becoming accepted as a valuable new tumor marker of poor prognosis. The second chapter, by Lee Bookstein and Lee, introduces the best known antioncogene, the retinoblas toma antioncogene, whose expression is sometimes lost in breast cancer. Malignant progression appears to be influenced by the balance of proto oncogene and antioncogene expression.
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Author: Sonia B. Jakowlew
Author: Sonia B. Jakowlew
Author: Jacqueline C. Newby
Author: Robin Baillie
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Author: Marc E. Lippman
Author: Mels Sluyser