Wnt5a and TGF-beta in mammary development and cancer

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。它已被证明，TGF-？s对正常乳腺发育和TGF-？信号传导对肿瘤进展和转移具有双相作用。在此之前，我们产生的转基因小鼠表达的TGF-？Ⅱ型受体（DNIIR）。在乳腺中表达DNIIR转基因的小鼠表现出在青春期增加的导管伸长和侧向分支，以及相对于野生型小鼠的肿瘤形成的改变。要确定基因在乳腺中的调节TGF-？并介导这些作用，我们进行了基于cDNA的微阵列比较野生型和DNIIR转基因乳腺中的基因表达。Wnt 5a被确定在筛选和调节Wnt 5a表达的TGF-？在体内和原代细胞培养中得到验证。Wnt 5a是特别感兴趣的，因为像TGF-β，它被认为是一种肿瘤抑制剂。此外，初步数据表明，与TGF-β一样，Wnt 5a限制乳腺的生长、导管延伸和侧向分支。然而，关于Wnt 5a在体内正常乳腺发育或肿瘤进展中的作用或机制知之甚少。我们假设，TGF-？调节Wnt 5a的表达，反过来介导至少一个子集的TGF-？的发育和肿瘤抑制作用。分析TGF-β的功能相互作用？和Wnt 5a以及Wnt 5a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进行：1）检验TGF-？和Wnt 5a信号传导协调以调节青春期期间的导管伸长和分支。2)确定Wnt 5a用于调节乳腺发育的信号传导途径，以及3）使用体内和外植体肿瘤模型来检验Wnt 5a抑制肿瘤生长和侵袭的假设。由于已经表明对Wnt 5a的应答依赖于细胞间相互作用，因此重要的是使用细胞-细胞和细胞-ECM相互作用完整的模型。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展。公共卫生相关性：乳腺癌是该国妇女中第二大常见癌症。每年，超过211，000名美国妇女得知她们患有这种疾病。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。它已被证明，放松管制的TGF-？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素，Wnt 5a，这是由TGF-？并可能介导其某些影响。我们建议表征TGF-？和Wnt 5a在正常乳腺发育和肿瘤进展中的作用。我们还建议确定Wnt 5a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展。这些研究的完成将产生有价值的信息，关于一个新的和高度相关的肿瘤抑制信号通路。

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.