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: 7992368
• 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/7992368
• 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育的许多方面的多功能因子组成。研究表明，TGF-β 对于正常乳腺发育至关重要，而 TGF-β 的失调则至关重要。信号传导对肿瘤进展和转移具有双相作用。此前，我们培育了表达 TGF-β 显性失活形式的转基因小鼠。 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导管伸长和侧向分支增加以及肿瘤形成的改变。鉴定乳腺中受 TGF-β 调节的基因为了调节这些效应，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TGF-β的筛选和调控Wnt5a表达中被鉴定出来。已在体内和原代细胞培养物中得到验证。 Wnt5a 受到特别关注，因为与 TGF-β 一样，它被认为可以充当肿瘤抑制因子。此外，初步数据表明，与 TGF-β 一样，Wnt5a 限制乳腺的生长、导管延伸和侧向分支。然而，对于 Wnt5a 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 又至少介导 TGF-β 的发育和肿瘤抑制作用的一部分。 TGF-β的功能相互作用分析和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具体目标中进行： 1）检验TGF-？和 Wnt5a 信号传导协调调节青春期导管的伸长和分支。 2) 确定 Wnt5a 用于调节乳腺发育的信号通路，以及 3) 使用体内和外植体肿瘤模型检验 Wnt5a 抑制肿瘤生长和侵袭的假设。由于有人认为对 Wnt5a 的反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非常重要。预计更好地了解调节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：乳腺癌是该国女性中第二常见的癌症类型。每年，超过 211,000 名美国女性得知她们患有这种疾病。转化生长因子-？多肽家族由控制生长和发育的许多方面的多功能因子组成。已经表明，TGF-β的放松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因子 Wnt5a，它受 TGF-β 调节。并可能调节其一些影响。我们建议表征 TGF-? 之间的功能相互作用。和Wnt5a在正常乳腺发育和肿瘤进展中的作用。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。预计更好地了解调节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有关新型且高度相关的肿瘤抑制信号通路的有价值的信息。