Integrin-Mediated Regulation of TGF-Beta Signaling and Tumorigenesis

描述（由申请人提供）：乳腺癌是美国女性癌症死亡的第二大原因。侵袭和转移是乳腺癌最致命的特征，也是乳腺癌相关死亡的主要原因。TGF - ?通常通过阻止乳腺上皮细胞（MEC）增殖或诱导MEC凋亡来抑制乳腺癌的发展。乳腺肿瘤发生抵消TGF-?的抑瘤活性，从而使TGF-？刺激乳腺癌的侵袭和转移。对于恶性mec如何克服TGF-的细胞抑制作用，我们的认识存在根本性的空白。，以及TGF-？刺激乳腺肿瘤的发展和发展。这些知识空白阻碍了科学和医学开发有效对抗TGF-？乳腺癌的发展和进展我们最近成立了？3整合素和Src作为TGF-？-刺激MAP激酶激活、细胞侵袭和上皮-间质转化（EMT）在正常和恶性mec中的作用。基于这些和其他初步发现，我们假设？v？3整合素和Src在乳腺癌中促进TGF-？以及它通过(i)诱导形成？v？3整合素:TGF - ?受体复合物;（ii）刺激TGF- I型（T¿R-I）和ii型（T¿R-II）受体的Tyr磷酸化；（iii）协调形成Shc:Grb2:Gab1/2复合物，通过TGF-¿放大MAP激酶的激活。一项推论表明，灭活av - 3整合素和Src功能将阻止TGF-¿从乳腺癌生长和侵袭的抑制因子向促进因子的转化，从而减轻TGF-¿刺激的乳腺癌的发生和进展。这些假设将通过三个具体目标来解决。特异性目标1将确定介导av - 3整合素：T - R-II复合物形成的3整合素和T - R-II决定因子，缺乏这些功能的突变体将用于确定av - 3整合素：T - R-II复合物在正常和恶性mec中介导TGF- -致癌信号传导的作用。Specific Aim 2将鉴定T¿R-I和T¿R-II中被Src磷酸化的Tyr残基，并使用缺乏这些功能的突变体来确定这些反应对正常和恶性mec中TGF-功能的影响。特异性Aim 3将确定阻断av - 3整合素和Src功能在阻止TGF-刺激小鼠乳腺癌细胞生长、侵袭、血管生成和转移中的有效性。这些研究将为TGF-¿如何促进乳腺癌的侵袭和转移提供有价值的信息，更重要的是，如何通过开发和使用av - 3整合素和Src拮抗剂来靶向TGF-¿的致癌活性来控制这些致命的过程。此外，我们的发现的应用将使科学和医学，有一天，改善转移性乳腺癌患者的预后和治疗。

DESCRIPTION (provided by applicant): Breast cancer is the second leading cause of cancer death in women in the United States. Invasion and metastasis are the most lethal characteristics of breast cancer and the leading cause of breast cancer-related death. TGF-? normally inhibits breast cancer development by preventing mammary epithelial cell (MEC) proliferation, or by inducing MEC apoptosis. Mammary tumorigenesis counteracts the tumor suppressing activities of TGF-?, thus enabling TGF-? to stimulate breast cancer invasion and metastasis. Fundamental gaps exist in our knowledge of how malignant MECs overcome the cytostatic actions of TGF-?, and of how TGF-? stimulates the development and progression of mammary tumors. These knowledge gaps have prevented science and medicine from developing treatments effective in antagonizing the oncogenic activities of TGF-? in developing and progressing breast cancers. We recently established ?v?3 integrin and Src as essential mediators of TGF-?-stimulated MAP kinase activation, cell invasion, and epithelial-to-mesenchymal transition (EMT) in normal and malignant MECs. Based on these and other preliminary findings, we hypothesize that aberrant activation of ?v?3 integrin and Src in developing breast cancers promotes the oncogenic function of TGF-? and its induction of breast cancer cell EMT, invasion, and metastasis by (i) inducing formation of ?v?3 integrin:TGF-? receptor complexes; (ii) stimulating Tyr phosphorylation of the TGF-¿ type I (T¿R-I) and type II (T¿R-II) receptors; and (iii) coordinating the formation Shc:Grb2:Gab1/2 complexes that amplify activation of MAP kinases by TGF-¿. A corollary states that inactivating av¿3 integrin and Src function will prevent the conversion of TGF-¿ from a suppressor to a promoter of breast cancer growth and invasion, thereby alleviating breast cancer development and progression stimulated by TGF-¿. Theses hypotheses will be addressed by three specific aims. Specific Aim 1 will identify the ¿3 integrin and T¿R-II determinants that mediate av¿3 integrin:T¿R-II complex formation and mutants lacking these functions will be used to establish the role of av¿3 integrin:T¿R-II complexes in mediating oncogenic signaling by TGF-¿ in normal and malignant MECs. Specific Aim 2 will identify the Tyr residues in T¿R-I and T¿R-II that are phosphorylated by Src and mutants lacking these functions will be used to determine the impact of these reactions on TGF-¿ function in normal and malignant MECs. Specific Aim 3 will determine the effectiveness of interdicting av¿3 integrin and Src function in preventing TGF-¿ stimulation of breast cancer cell growth, invasion, angiogenesis, and metastasis in mice. These studies will provide valuable information on how TGF-¿ promotes breast cancer invasion and metastasis, and more importantly, on how to control these deadly processes by targeting the oncogenic activities of TGF-¿ through the development and use of av¿3 integrin and Src antagonists. Moreover, application of our findings will enable science and medicine to, one day, improve the prognosis and treatment of patients with metastatic breast cancer.