Integrin-mediated Regulation of TGFbeta Signaling and Tumorigenesis

整合素介导的 TGFbeta 信号传导和肿瘤发生的调节

• 批准号: 8883400
• 负责人: William Schiemann
• 金额: $ 28.94万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-11 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8883400
• 关键词: Address; Antimetastatic Agent; Apoptosis; Atypia; Automobile Driving; BRCA1 gene; Biological Markers; Breast; Breast Cancer Model; Breast Cancer Patient; Breast Epithelial Cells; Breast cancer metastasis; Cancer Etiology; Carcinoma; Cells; Cessation of life; Characteristics; Clinical; Complex; Comprehensive Cancer Center; Coupled; Coupling; Defect; Development; Diagnostic; Dinoprostone; Disease; E-Cadherin; ERBB2 gene; Epigenetic Process; Epithelial Cell Proliferation; Estrogens; Event; Evolution; Exhibits; Failure; Family member; Fine needle aspiration biopsy; Focal Adhesions; Funding; Gene Expression Profile; Genetic; Hormonal; Hormone Receptor; Human; Image; In Vitro; Individual; Integrins; Knowledge; Laboratories; Lead; MAP3K7 gene; MAP3K7IP1 gene; Magnetic Resonance Imaging; Mammary Gland Parenchyma; Mammary Tumorigenesis; Maps; Mediating; Medicine; Methylation; Mitogen-Activated Protein Kinases; Molecular; Monitor; Neoplasm Metastasis; Normal Range; Oncogenic; Outcome; PTK2 gene; Pathway interactions; Patients; Pharmacologic Substance; Pharmacotherapy; Phenotype; Predictive Value; Process; Progesterone; Protein-Lysine 6-Oxidase; Proteins; Recurrence; Regulation; Relapse; Role; Sampling; Science; Signal Pathway; Signal Transduction; Staging; Stem cells; Survival Rate; System; Tissue Microarray; Tissue Sample; Transforming Growth Factor beta; Transforming Growth Factors; Translating; Tumor Promoters; Tumor Subtype; Tumor Suppressor Proteins; United States; Woman; Xenograft Model; base; bead chip; cancer stem cell; chemotherapy; chromatin immunoprecipitation; cytokine; effective therapy; epigenetic marker; human BCAR1 protein; improved; in vivo; innovation; insight; malignant breast neoplasm; novel; outcome forecast; parent grant; prevent; response; spatiotemporal; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer is a heterogeneous disease comprised of at least 5 major tumor subtypes that coalesce as the second leading cause of cancer death in women in the United States. Amongst individual breast cancer subtypes, those classified as being triple-negative breast cancers (TNBCs) are clinically unique via their presentation of aggressive and metastatic phenotypes, and their high propensity to recur rapidly following conventional chemotherapy treatment. TNBCs are also noteworthy by their failure to express hormone receptors (estrogen and progesterone) and ErbB2/HER2, a phenotype that renders targeted chemotherapies (e.g., hormonal or HER2-directed) ineffective and contributes to the poor prognosis of TNBC patients. Although our understanding of the molecular features and clinical manifestations of TNBCs has increased in recent years, science and medicine still lack sufficient knowledge of TNBC development and progression to permit the synthesis of novel pharmaceuticals capable of specifically targeting and alleviating this lethal breast cancer subtype. Transforming growth factor-ß (TGF-ß) is a powerful suppressor of mammary tumorigenesis. Interestingly, late-stage TNBCs respond to TGF-ß as if this cytokine were a tumor promoter, leading to the acquisition of metastatic and stem cell phenotypes. Although the molecular mechanisms underlying the conversion of TGF-ß function from that of a tumor suppressor to a tumor promoter in TNBCs remains incompletely understood, our laboratory recently defined a novel integrin-based signaling module that facilitates oncogenic TGF-ß signaling in TNBCs. Along these lines, we find the expression and activity of lysyl oxidase (LOX) to contribute to oncogenic TGF-ß signaling in part due to alterations in mechanotransduction. Based on these and other preliminary findings, we hypothesize that integrin switching underlies metastatic progression of TNBCs driven TGF-ß. A corollary states that developing novel chemotherapeutics to prevent integrin switching and oncogenic TGF-ß signaling will significantly improve the overall survival rates of TNBC patients. These hypotheses will be addressed by four Specific Aims. Aim 1 will determine the role of integrins and focal adhesion complexes during initiation of the "TGF-ß Paradox" by mechanotransduction. We will manipulate, both positively and negatively, the expression of B1 and B3 integrin and their effectors to gauge their function in coupling mechanotransduction to the oncogenic activities of TGF-ß both in vitro and in vivo. Likewise, the ability of mechanotransduction and Smad2/3 signaling to epigenetically silence E-cadherin expression during TNBC metastasis will be assessed. Aim 2 will determine the role of LOX family members in mediating oncogenic TGF-ß signaling in TNBCs. Additionally, genetic and pharmacological inactivation of LOX family members will be undertaken to assess their function in driving TNBC metastasis stimulated by TGF-ß. Aim 3 will map the transcriptome and epigenetic events coupled to TNBC development and metastatic progression. The presence of identified epigenetic marks in patient breast cells isolated by random periareolar fine needle aspiration will be determined to assess their utility as predictive TNBC biomarkers. Lastly, Aim 4 will visualize TGF-ß signaling during metastatic progression of TNBCs through the use of dual bioluminescent imaging. Simultaneous CTL1-based MRI approaches will be employed to monitor corresponding changes in tumor reactive stroma, as well as determine how conventional chemotherapies impact these metastatic events. Collectively, these studies will provide valuable information on how TGF-ß, integrins, and mechanotransduction cooperate in promoting the EMT, invasion, and metastasis of TNBCs, and more importantly, on how to control these deadly processes by inactivating the oncogenic activities of TGF-ß. Moreover, translating our epigenetic biomarkers to clinical diagnostic applications will enable science and medicine to significantly improve the overall survival of patients with TNBCs.

描述(申请人提供)：乳腺癌是一种异质性疾病，由至少5种主要肿瘤亚型组成，是美国女性癌症死亡的第二大原因。在个体乳腺癌亚型中，那些被归类为三阴性乳腺癌(TNBCs)的乳腺癌在临床上是独一无二的，因为他们表现出侵袭性和转移性的表型，以及他们在常规化疗后迅速复发的高倾向。值得注意的是，TNBCs不表达激素受体(雌激素和孕激素)和ErbB2/HER2，这一表型使靶向化疗(如激素或HER2)无效，并导致TNBC患者预后不良。尽管近年来我们对TNBCs的分子特征和临床表现的了解有所增加，但科学和医学仍然缺乏对TNBC的发展和进展的足够了解，无法合成能够特异性靶向和缓解这一致命乳腺癌亚型的新药物。转化生长因子是一种强有力的乳腺肿瘤抑制因子。有趣的是，晚期TNBCs对转化生长因子的反应就像这种细胞因子是肿瘤促进剂一样，导致转移和干细胞表型的获得。尽管TNBCs中转化生长因子β功能从肿瘤抑制因子向肿瘤促进剂转化的分子机制尚不完全清楚，但我们的实验室最近定义了一个新的基于整合素的信号模块，该模块可促进肿瘤细胞中的转化生长因子β信号转导。沿着这些途径，我们发现赖氨酰氧化酶(LOX)的表达和活性在一定程度上是由于机械转导的改变而对致癌的转化生长因子-伯信号转导做出贡献。基于这些和其他初步发现，我们假设整合素的转换是TNBCs驱动的转化生长因子的转移进展的基础。一个推论是，开发新的化疗药物来防止整合素转换和致癌的转化生长因子-伯信号转导将显著提高TNBC患者的总体存活率。这些假设将通过四个具体目标来解决。目的1将确定整合素和焦点黏附复合体在通过机械转导启动“转化生长因子--贝悖论”过程中的作用。我们将积极和消极地操纵B1和B3整合素及其效应器的表达，以评估它们在体外和体内将机械转导与转化生长因子-B的致癌活性偶联的功能。同样，将评估机械转导和Smad2/3信号在TNBC转移过程中表观遗传沉默E-钙粘蛋白表达的能力。目的2将确定LOX家族成员在TNBCs中介导致癌的转化生长因子-β信号转导中的作用。此外，还将对LOX家族成员进行遗传和药物失活，以评估它们在推动转化生长因子-B刺激的TNBC转移中的作用。目标3将绘制转录组和表观遗传学事件图，这些事件与TNBC的发育和转移进展有关。通过随机乳晕周围细针抽吸分离的患者乳腺细胞中是否存在已识别的表观遗传标记，将被确定为评估它们作为预测TNBC生物标记的有效性。最后，AIM 4将通过使用双生物发光成像技术，可视化TNBCs转移进展过程中的转化生长因子-？信号。同时基于CTL1的MRI方法将被用来监测肿瘤反应性间质的相应变化，以及确定传统化疗如何影响这些转移事件。总之，这些研究将提供关于转化生长因子、整合素和机械转导如何协同促进TNBCs的EMT、侵袭和转移的有价值的信息，更重要的是，关于如何通过灭活转化生长因子-β的致癌活性来控制这些致命过程。此外，将我们的表观遗传生物标记物转化为临床诊断应用将使科学和医学能够显著提高TNBCs患者的总体存活率。