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

描述(由申请人提供)：进一步了解转化生长因子-β信号通路在乳腺癌发生中的作用将导致新的人类治疗方法的确定。转化生长因子-β信号在一定程度上受辅助受体--III型转化生长因子受体(T？RIII)的调节。此外，可溶性T？RIII(ST？RIII)通过T？RIII受体的胞外结构域脱落而产生，通过隔离配体来抑制转化生长因子-β信号转导，导致转化生长因子-β信号转导的下调。在早期乳腺肿瘤中，转化生长因子-β作为肿瘤抑制因子发挥作用，而在晚期肿瘤中，转化生长因子-β信号具有促肿瘤作用。T？RIII表达缺失是乳腺癌中常见的早期事件，T？RIII表达的恢复抑制了肿瘤的侵袭、血管生成和转移，支持T？RIII作为乳腺癌的肿瘤抑制因子。T？RIII的抑癌作用可能部分是由于ST？RIII的产生，而ST？RIII拮抗了晚期乳腺肿瘤中转化生长因子-β信号的促癌作用。然而，这表明在乳腺癌发生之前增加T？RIII的表达可能会促进肿瘤的发生，这是因为ST？RIII的表达增加，随后TGF-β信号的下调。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。本研究旨在利用在乳腺中过度表达T？RIII的MMTV-T？RIII小鼠模型，确定T？RIII在乳腺发育中的作用，并进一步研究其在乳腺癌发生发展中的作用。这将通过四个具体目标来解决：(1)确定MMTV-T？RIII小鼠是否表现出乳腺发育加速。(2)确定MMTV-T？RIII小鼠是否表现出循环中ST？RIII水平升高和转化生长因子-β信号降低。(3)通过评估癌基因(与MMTV-HER2/neu小鼠杂交)和化学致癌物(DMBA)诱导的MMTV-T？RIII小鼠的肿瘤形成，确定T？RIII表达增加是否促进了乳腺癌的发生，但抑制了肿瘤的进展。(4)确定T？RIII是否通过抑制肿瘤的定向迁移和侵袭而发挥抑制肿瘤进展的作用。公共健康相关性：确定T？RIII在乳腺癌发生中的作用将确定其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，并帮助靶向治疗不同阶段的乳腺癌的转化生长因子-β信号通路。

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.