Elucidating the Role of the TGF-Beta Receptor III in Breast Carcinogenesis

描述（由申请人提供）：进一步了解TGF-¿信号通路在乳腺癌发生中的作用，将有助于发现新的人类治疗方法。TGF-信号在一定程度上由一种共同受体调节，即III型TGF-受体（T - RIII）。此外，可溶性T¿RIII （sT¿RIII）通过T¿RIII受体的外胞域脱落产生，通过隔离配体抑制TGF-¿信号转导，导致TGF-¿介导的信号转导下调。在早期乳腺肿瘤中TGF-¿具有抑瘤作用，而在晚期肿瘤中TGF-¿信号具有促瘤作用。T¿RIII表达缺失是人类乳腺癌中常见的早期事件，T¿RIII表达的恢复抑制肿瘤侵袭、血管生成和转移，支持T¿RIII在乳腺癌中的抑癌作用。T¿RIII的抑瘤功能似乎部分是由于sT¿RIII的产生，它在晚期乳腺肿瘤中拮抗TGF-¿信号的促瘤作用。然而，这表明在乳腺癌发生前增加T¿RIII的表达可能由于sT¿RIII的表达增加和随后TGF-¿信号的下调而促进肿瘤的发生。相反，在晚期乳腺肿瘤中，T¿RIII通过sT¿RIII的产生，通过限制肿瘤的侵袭和迁移来抑制肿瘤的进展。本研究旨在确定T¿RIII在乳腺发育中的作用，并利用MMTV-T¿RIII小鼠模型进一步表征其在乳腺癌发生和进展中的作用，该模型在乳腺中过表达T¿RIII。这将通过四个具体目标来解决：(1)确定MMTV-T¿RIII小鼠是否表现出加速的乳腺发育。(2)确定MMTV-T¿RIII小鼠是否表现出循环中sT¿RIII水平升高和TGF-¿信号传导降低。(3)通过评估致癌基因（与MMTV-her2/neu小鼠交叉）和化学致癌物（DMBA）诱导MMTV-T - RIII小鼠的肿瘤发生，确定T¿RIII表达增加是否促进了乳腺癌的发生，但抑制了癌症的进展。(4)确定T¿RIII是否通过抑制定向迁移和侵袭来发挥其对肿瘤进展的抑制作用。公共卫生相关性：确定T øⅲ在乳腺癌发生中的作用将确定其作为治疗人类乳腺癌的潜在治疗靶点。这些研究将确定T¿RIII过表达对乳腺癌发生和发展的影响，确定T¿RIII和sT¿RIII作为人类治疗的潜在靶点，并有助于靶向TGF-¿信号通路治疗不同阶段的人类乳腺癌。

DESCRIPTION (provided by applicant): Further understanding the role of the TGF-¿ signaling pathway in breast carcinogenesis will lead to the identification of new human therapeutic treatments. TGF-¿ signaling is regulated in part by a co-receptor, the type III TGF-¿ receptor (T¿RIII). In addition, soluble T¿RIII (sT¿RIII), which is generated through ectodomain shedding of the T¿RIII receptor, inhibits TGF-¿ signaling by sequestering ligand, resulting in the down-regulation of TGF-¿ mediated signaling. In early stage breast tumors TGF-¿ functions as a tumor suppressor, while in late-stage tumors TGF-¿ signaling has a tumor promoting effect. The loss of T¿RIII expression is a frequent early event in human breast cancers and the restoration of T¿RIII expression inhibits tumor invasion, angiogenesis, and metastasis, supporting T¿RIII as a tumor suppressor in breast cancer. The tumor suppressor function of T¿RIII appears to be due, in part, to the generation of sT¿RIII, which antagonizes the tumor promoting effects of TGF-¿ signaling in late stage mammary tumors. However, this suggests that increasing T¿RIII expression prior to the initiation of mammary carcinogenesis may promote tumorigenesis due to the increased expression of sT¿RIII and subsequent down-regulation of TGF-¿ signaling. Conversely, during late-stage mammary tumors, T¿RIII, through sT¿RIII production, inhibits tumor progression by limiting tumor invasion and migration. This study aims to determine the role of T¿RIII in mammary gland development and to further characterize its effects on the initiation and progression of mammary carcinogenesis by utilizing the MMTV-T¿RIII mouse model, which over-expresses T¿RIII in the mammary gland. This will be addressed by four specific aims: (1) Establish whether MMTV-T¿RIII mice exhibit accelerated mammary gland development. (2) Establish whether MMTV-T¿RIII mice exhibit elevated circulating levels of sT¿RIII and decreased TGF-¿ signaling. (3) Establish whether increased T¿RIII expression promotes mammary cancer initiation, but inhibits cancer progression through the assessment of oncogene (cross to MMTV-her2/neu mice) and chemical carcinogen (DMBA) induced tumorigenesis in MMTV-T¿RIII mice. (4) Establish whether T¿RIII exerts its inhibitory effects on tumor progression through the inhibition of directed migration and invasion. PUBLICL HEALTH RELEVANCE: Defining the role of the T¿RIII in mammary carcinogenesis will identify it as a potential therapeutic target for the treatment of human breast cancer. These studies will determine the effects of T¿RIII over-expression on breast cancer initiation and progression, identify T¿RIII and sT¿RIII as potential targets for human therapeutic treatments, and aid in targeting of the TGF-¿ signaling pathway for the treatment of various stages of human breast cancers.