Wnt5a and TGF-beta in mammary development and cancer

Wnt5a 和 TGF-β 在乳腺发育和癌症中的作用

• 批准号: 8196812
• 负责人: Rosa A. Serra
• 金额: $ 29.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-21 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8196812
• 关键词: Adult; Affect; American; Biological Assay; Birth; Breast; Breast Cancer Treatment; Cell Adhesion Process; Cell Culture Techniques; Cell Polarity; Cells; Complementary DNA; Complex; Country; Data; Development; Disease; Dominant-Negative Mutation; Ductal; Epithelial Cells; Extracellular Matrix; Family; Gene Expression; Genes; Goals; Growth; Growth and Development function; Health; Implant; Kidney; Knockout Mice; Laboratories; Lateral; Learning; Malignant Neoplasms; Mammary gland; Measures; Mediating; Metallothionein; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Newborn Infant; Pathology; Pathway interactions; Phosphotransferases; Physiology; Polyoma Virus Middle T Staining Method; Primary Cell Cultures; Protein-Serine-Threonine Kinases; Proteins; Puberty; Recombinants; Regulation; Relative (related person); Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Testing; Tissues; Transforming Growth Factor beta; Transgenes; Transgenic Mice; Transgenic Organisms; Transplantation; Tumor Cell Invasion; Tumor Suppressor Proteins; Wild Type Mouse; Woman; base; cancer type; capsule; carcinogenesis; cell growth; cell type; discoidin receptor; in vivo; interest; loss of function; malignant breast neoplasm; mammary epithelium; mammary gland development; member; novel; polypeptide; promoter; receptor; research study; response; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): The TGF-? family of polypeptides consists of multifunctional factors that control many aspects of growth and development. It has been shown that TGF-?s are critical for normal mammary development and that dysregulation of TGF-? signaling has a biphasic effect on tumor progression and metastasis. Previously, we generated transgenic mice that express a dominant-negative form of the TGF-? type II receptor (DNIIR). Mice expressing the DNIIR transgene in the mammary gland demonstrated increased ductal elongation and lateral branching during puberty and alterations in tumor formation relative to wild type mice. To identify genes in the mammary gland that are regulated by TGF-? and mediate these effects, we performed cDNA based microarrays comparing gene expression in wild type and DNIIR transgenic mammary glands. Wnt5a was identified in the screen and regulation of Wnt5a expression by TGF-? was verified in vivo and in primary cell culture. Wnt5a is of special interest because, like TGF-?, it has been suggested to act as a tumor suppressor. Furthermore, preliminary data suggest that, like TGF-?, Wnt5a limits growth, ductal extension, and lateral branching in the mammary gland. Nevertheless, very little is known about the role or mechanism of Wnt5a action in normal mammary gland development or tumor progression in vivo. We hypothesize that TGF-? regulates the expression of Wnt5a, which in turn mediates at least a subset of TGF-?'s developmental and tumor suppressive effects. Analysis of the functional interactions of TGF-? and Wnt5a as well as the role and mechanism of Wnt5a action in normal mammary gland development and tumor progression will be undertaken in the following specific aims: 1) To test the hypothesis that TGF-? and Wnt5a signaling are coordinated to regulate ductal elongation and branching during puberty. 2) To determine the signaling pathways used by Wnt5a to regulate mammary development, and 3) To test the hypothesis that Wnt5a inhibits tumor growth and invasion using in vivo and explant tumor models. Since it has been suggested that the response to Wnt5a relies on intercellular interactions, it is important to use models in which cell-cell and cell-ECM interactions are intact. It is anticipated that a better understanding of the genes that regulate mammary development will promote advances in breast cancer treatment. PUBLIC HEALTH RELEVANCE: Breast cancer is the second most common type of cancer among women in this country. Each year, more than 211,000 American women learn they have this disease. The TGF-? family of polypeptides consists of multifunctional factors that control many aspects of growth and development. It has been shown that deregulation of TGF-? signaling has a biphasic effect on tumor progression and metastasis. We have identified another factor, Wnt5a, which is regulated by TGF-? and may mediate some of its effects. We propose to characterize functional interactions between TGF-? and Wnt5a in normal mammary development and tumor progression. We also propose to determine the role and mechanism of Wnt5a action in normal breast physiology and pathology. It is anticipated that a better understanding of the genes that regulate mammary development will promote advances in breast cancer treatment. Completion of these studies will yield valuable information regarding a novel and highly relevant tumor-suppressor signaling pathway.

描述（由申请人提供）：TGF-？多肽家族由控制生长和发展的许多方面的多功能因素组成。已经表明，TGF- s对于正常的乳腺发育和TGF-的失调至关重要？信号传导对肿瘤进展和转移具有双相作用。以前，我们产生了表达TGF-的显性阴性形式的转基因小鼠？ II型受体（DNIIR）。表达乳腺中DNIIR转基因的小鼠表明，相对于野生型小鼠，青春期期间的导管伸长和横向分支增加以及肿瘤形成的改变。鉴定受TGF-调控的乳腺中的基因？并介导了这些作用，我们进行了基于cDNA的微阵列，比较了野生型和DNIIR转基因乳腺中的基因表达。 Wnt5a在屏幕上鉴定出Wnt5a和通过TGF-的WNT5A表达调节？在体内和原发性细胞培养中得到了验证。 Wnt5a具有特别的兴趣，因为像TGF-？一样，它被建议用作肿瘤抑制剂。此外，初步数据表明，像TGF-？，Wnt5a一样，乳腺中的生长，导管延伸和侧向分支。然而，关于Wnt5a作用在正常乳腺发育或体内肿瘤进展中的作用或机制知之甚少。我们假设TGF-？调节Wnt5a的表达，而Wnt5a的表达至少介导了TGF-的发育和肿瘤抑制作用的一部分。分析TGF-的功能相互作用？ Wnt5a以及Wnt5a作用在正常乳腺发育和肿瘤进展中的作用和机制将在以下特定目的中进行：1）检验TGF-的假设？ WNT5A信号传导是协调的，以调节青春期期间的导管伸长和分支。 2）确定WNT5A用于调节乳腺发育的信号传导途径，以及3）测试WNT5A抑制使用体内和Epplant肿瘤模型的肿瘤生长和侵袭的假设。由于已经提出对WNT5A的响应依赖于细胞间相互作用，因此使用细胞细胞和细胞ECM相互作用完整的模型很重要。可以预计，对调节乳腺发育的基因有更好的了解将促进乳腺癌治疗的进展。公共卫生相关性：乳腺癌是该国妇女中第二常见的癌症类型。每年，超过211,000名美国妇女都知道自己患有这种疾病。 TGF-？多肽家族由控制生长和发展的许多方面的多功能因素组成。已经显示出TGF-的管制？信号传导对肿瘤进展和转移具有双相作用。我们已经确定了另一个受TGF-调节的因素Wnt5a？并可能调解其一些影响。我们建议表征TGF-之间的功能相互作用？和正常乳腺发育和肿瘤进展中的Wnt5a。我们还建议确定WNT5A作用在正常乳腺生理和病理学中的作用和机制。可以预计，对调节乳腺发育的基因有更好的了解将促进乳腺癌治疗的进展。这些研究的完成将产生有关新型且高度相关的肿瘤抑制信号传导途径的宝贵信息。