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)：该转化生长因子？多肽家族由多种功能因子组成，控制着生长发育的许多方面。已有研究表明，转化生长因子-β-S是乳腺正常发育的关键，转化生长因子-β-β的异常调节是乳腺发育的重要机制之一。信号在肿瘤进展和转移中具有双相效应。此前，我们培育的转基因小鼠表达显性-阴性形式的转化生长因子？II型受体(DNIIR)。与野生型小鼠相比，在乳腺中表达DNIIR转基因的小鼠在青春期表现出更多的导管延长和侧向分支，以及肿瘤形成的变化。目的：确定乳腺中受转化生长因子-β？并通过基因芯片比较野生型和DNIIR转基因乳腺中的基因表达。Wnt5A在筛选中被鉴定并被转化生长因子调节。在体内和原代细胞培养中都得到了验证。WNT5A之所以特别令人感兴趣，是因为它和转化生长因子-β一样，被认为是一种肿瘤抑制因子。此外，初步数据表明，与转化生长因子-β一样，WNT5a限制了乳腺的生长、导管延伸和侧枝。然而，关于WNT5a在体内正常乳腺发育或肿瘤进展中的作用或机制还知之甚少。我们假设转化生长因子-？调节Wnt5a的表达，而Wnt5a反过来又至少介导转化生长因子-β的一部分，S的发育和肿瘤抑制作用。转化生长因子-？功能相互作用分析Wnt5a以及Wnt5a在正常乳腺发育和肿瘤进展中的作用和机制将在以下方面进行具体的研究：1)验证假设：和Wnt5a信号相互协调，调节青春期导管的伸长和分支。2)确定Wnt5a调控乳腺发育的信号通路；3)利用体内和外植性肿瘤模型验证Wnt5a抑制肿瘤生长和侵袭的假说。由于已经提出对WNT5a的反应依赖于细胞间的相互作用，因此使用细胞-细胞和细胞-ECM相互作用完整的模型是很重要的。预计更好地了解调控乳腺发育的基因将促进乳腺癌治疗的进步。公共卫生相关性：乳腺癌是这个国家女性中第二常见的癌症类型。每年，超过211,000名美国妇女得知她们患有这种疾病。转化生长因子-？多肽家族由多种功能因子组成，控制着生长发育的许多方面。已有研究表明，放松对转化生长因子-1的调控。信号在肿瘤进展和转移中具有双相效应。我们已经确定了另一个因子，Wnt5a，它受转化生长因子-？并可能调解它的一些影响。我们建议描述转化生长因子-？Wnt5a与正常乳腺发育和肿瘤进展有关。我们还建议确定WNT5a在正常乳腺生理和病理中的作用和机制。预计更好地了解调控乳腺发育的基因将促进乳腺癌治疗的进步。这些研究的完成将产生关于新的和高度相关的肿瘤抑制信号通路的有价值的信息。