Latent TGF-beta Binding Protein in Mammary Development and Tumorigenesis

乳腺发育和肿瘤发生中的潜在 TGF-β 结合蛋白

• 批准号: 7618374
• 负责人: Alicia Pinderhughes
• 金额: $ 4.1万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618374
• 关键词: Apoptosis; Binding; Binding Proteins; Biological Availability; Breast; Breast Cancer Model; Cells; Deposition; Development; Developmental Process; Diagnostic Neoplasm Staging; Extracellular Matrix; Fibrosis; Growth; Knowledge; Link; Localized; Maintenance; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Modeling; Mus; Neoplasm Metastasis; Proliferating; Radiation; Regulation; Role; Stem cells; Tissues; Transforming Growth Factors; epithelial to mesenchymal transition; experience; in vivo; latent TGF-beta binding protein; loss of function; malignant breast neoplasm; neoplastic cell; protein function; receptor; tumor; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Latent Transforming Growth Factor-¿ (TGF-¿) Binding Protein (LTBP) is bound to TGF-P and is essential in most cells for its proper folding and secretion. In addition, LTBP localizes TGF-¿ to the extracellular matrix and helps maintain its latency until activated. TGF-¿ has many functions that have relevance to breast cancer, including growth inhibition, regulation of apoptosis, maintenance of stem cell quiescence, promotion of epithelial-to-mesenchymal transition, and extracellular matrix deposition during radiation-induced-fibrosis. There are three TGF-¿s, all of which are expressed in the breast, and though they share the same receptors, they have distinct in vivo functions. In addition, there are three different LTBPs that can bind TGF- ¿, but nothing is known about the function of these proteins the in the mammary gland. Given the significance of TGF-¿ to both inhibition of tumor development and promotion of breast tumor metastasis, and LTBP's role as a regulator of TGF-¿, this proposal aims to determine the effects of loss of LTBP function on TGF-¿ activation and murine models of breast cancer. Due to lack of knowledge about LTBPs in breast and established links between misregulation of developmental processes and cancer development, I also propose to determine LTBP expression and loss-of-function effects during murine models of breast development. Relevance TGF-¿ is intimately linked to breast cancer in several ways: in early stage cancers, it inhibits cells from proliferating, providing protection from tumor progression; in late stage cancers, it promotes metastasis of tumor cells; it also contributes to fibrosis experienced after radiation treatment. LTBPs regulate TGF-¿ in other tissues, but nothing is known about their function in the breast. This project aims to understand LTBP expression and functions during breast development and cancer.

描述（由申请人提供）：潜在转化生长因子-β（TGF-β）结合蛋白（LTBP）与TGF-β结合，在大多数细胞中对其正确折叠和分泌至关重要。此外，LTBP将TGF-β定位于细胞外基质，并帮助维持其潜伏期直至激活。TGF-β具有许多与乳腺癌相关的功能，包括生长抑制、细胞凋亡调节、维持干细胞静止、促进上皮向间充质转化和辐射诱导纤维化期间的细胞外基质沉积。有三种TGF-β，它们都在乳腺中表达，尽管它们共享相同的受体，但它们在体内具有不同的功能。此外，有三种不同的LTBP可以结合TGF-β，但对这些蛋白质在乳腺中的功能一无所知。鉴于TGF-β对抑制肿瘤发展和促进乳腺肿瘤转移的重要性，以及LTBP作为TGF-β调节剂的作用，本提案旨在确定LTBP功能丧失对TGF-β活化和乳腺癌小鼠模型的影响。由于缺乏对乳腺LTBP的了解，以及发育过程中的失调与癌症发展之间的联系，我还建议在乳腺发育的小鼠模型中确定LTBP的表达和功能丧失的影响。相关性TGF-â在几个方面与乳腺癌密切相关：在早期癌症中，它抑制细胞增殖，防止肿瘤进展;在晚期癌症中，它促进肿瘤细胞转移;它还有助于放射治疗后经历的纤维化。LTBPs调节其他组织中的TGF-β，但对它们在乳腺中的功能一无所知。该项目旨在了解LTBP在乳腺发育和癌症过程中的表达和功能。