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，正如我们在最近的一篇综述中指出的那样，IR对正常组织微环境的全球影响也可能具有重要的临床意义。细胞外基质(ECM)已被证明通过其受体如整合素介导信号，并对维持正常组织结构至关重要，这一特征在恶性表型中被从根本上破坏。？？1整合素信号与乳腺癌的进展有关，此外，在几种人类癌症中，整合素信号被证明促进了对化疗和IR的抵抗。我们以前已经证明，在三维层粘连蛋白富含基质(3DlrECM)培养的乳腺上皮细胞中，IR暴露后，β1整合素的表达以可遗传的和持续的方式异常上调。我的初步研究表明，在3DlrECM培养模型和体内，1整合素抑制导致乳腺癌细胞株的凋亡增加和增殖减少，对动物没有明显的毒性。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β1整合素表达增加是无复发和5年和10年总生存率的预后因素(附录IV)。在目前的建议中，我们的初步数据表明，1整合素抑制增强了IR在3DlrECM和体内的治疗效果；这些有希望的发现可能会影响患者的临床放疗。我们假设？1整合素通过Akt介导IR后支持生存的信号，该信号可作为治疗的靶点。因此，这项建议的主要焦点将是使用浸润性乳腺癌和导管原位癌(DCIS)的3D lrECM培养模型来研究IR诱导的β1整合素信号是否通过Akt介导的生存信号，并在体内肿瘤微环境的背景下扩展Akt介导的β1整合素信号在IR后的生存效应。

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.