Manipulating b1 integrin to enhance radiation therapy for breast cancer

描述（由申请人提供）：历史上，研究集中在电离辐射（IR）通过DNA损伤和细胞凋亡消除癌细胞来根除肿瘤的能力。 然而，正如我们在最近的综述中所指出的，IR对正常组织微环境的全球后果也可能具有重要的临床意义。细胞外基质（ECM）已被证明介导的信号通过其受体，如？1整联蛋白，并且对维持正常组织结构至关重要，这是恶性表型中根本性破坏的特征。?? 1整联蛋白信号转导与乳腺癌进展有关，此外，已显示在几种人类癌症中促进对化疗和IR的抗性。 我们之前已经证明了？1整联蛋白表达在IR暴露后以可遗传和持续的方式在三维层粘连蛋白富集基质（3D lrECM）中培养的乳腺上皮细胞中异常上调。 我的初步研究表明？1整联蛋白抑制导致在3D lrECM培养模型和体内乳腺癌细胞系中细胞凋亡增强和增殖减少，对动物没有可辨别的毒性。 重要的是，在一项对早期浸润性乳腺癌患者的研究中，我们发现，1整合素表达是5年和10年无复发和总生存期的预后指标（附录IV）。在目前的建议中，我们的初步数据表明，？1整联蛋白抑制增强了IR在3DlrECM和体内的治疗功效;这些有希望的发现有可能影响患者的临床RT。我们假设？1整联蛋白介导的促存活信号后，IR通过Akt，可以靶向治疗。 因此，本提案的主要重点将是调查IR是否诱发？1整合素信号通过Akt介导的生存信号，使用三维lrECM培养模型的浸润性乳腺癌和导管原位癌（DCIS），并扩大后Akt介导的生存影响？1整合素信号传导后IR在体内肿瘤微环境的背景下。

DESCRIPTION (provided by applicant): Historically, research has focused on the ability of ionizing radiation (IR) to eradicate the tumor by eliminating cancer cells through DNA damage and apoptosis. However, as we have pointed out in a recent review, the global consequences of IR on the normal tissue microenvironment can also have important clinical implications. Extracellular matrix (ECM) has been shown to mediate signaling through its receptors such as ?1 integrin and is critical to maintenance of normal tissue structure, a feature that is fundamentally disrupted in the malignant phenotype. ??1 integrin signaling has been implicated in breast cancer progression, and, in addition, has been shown to facilitate resistance to chemotherapy and IR in several human cancers. We have shown previously that ?1 integrin expression is aberrantly up regulated after IR exposure in a heritable and persistent manner in mammary epithelial cells cultured in a 3-dimensional laminin rich matrix (3D lrECM). My initial studies have shown that ?1 integrin inhibition resulted in enhanced apoptosis and decreased proliferation among breast cancer cell lines in the 3D lrECM culture model and in vivo with no discernible toxicity to animals. Importantly, in a study of early stage invasive breast cancer patients, we found that increased ?1 integrin expression was prognostic for recurrence-free and overall survival at 5 and 10 years (Appendix IV). In the present proposal, our preliminary data demonstrates that ?1 integrin inhibition enhances the therapeutic efficacy of IR in 3DlrECM and in vivo; these promising findings have the potential to impact clinical RT for patients. We hypothesize that ?1 integrin mediates a pro-survival signal after IR via Akt that can be targeted for therapy. The primary focus of this proposal therefore will be to investigate if IR induced ?1 integrin signaling mediates a survival signal via Akt using 3D lrECM culture models of invasive breast cancer and ductal carcinoma in situ (DCIS) and to expand upon the Akt-mediated survival effects of ?1 integrin signaling post-IR in the context of the tumor microenvironment in vivo.