Integrin Function and Signaling in Carcinoma Progression

整合素在癌症进展中的功能和信号传导

• 批准号: 7464821
• 负责人: Arthur M Mercurio
• 金额: $ 33.57万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7464821
• 关键词: A Mouse; Actin-Binding Protein; Actins; African American; Aggressive behavior; Alanine; BRCA1 gene; Basement membrane; Biology; Breast; Breast Carcinoma; Carcinoma; Cell Line; Cell physiology; Cells; Class; Clinical Management; Data; Development; Disease; ERBB2 gene; Epithelial Cells; Epithelium; F-Actin; Funding; Gene Cluster; Gene Expression; Genes; Goals; Grant; Hemidesmosomes; Human; Immigration; Integrins; Invasive; Learning; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Mus; Mutate; Mutation; Phase; Phosphorylation; Premenopause; Property; Proteins; Public Health; Receptor Signaling; Recurrence; Seminal; Serine; Signal Transduction; Structure; Transgenic Organisms; Woman; Work; Wound Healing; base; cell motility; cohort; defined contribution; fascin; in vivo; insight; malignant breast neoplasm; member; migration; mouse model; prognostic; prototype; tool; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): The overall goal of this renewal continues to be the study of the integrin ?4?6 (referred to as `?4') as an approach for elucidating mechanisms involved in the genesis and progression of breast carcinoma, and for identifying targets for the clinical management of this disease. This integrin anchors basal epithelial cells to the basement membrane in inert structures termed hemidesmosomes (HDs). A seminal finding made in work funded by this grant is that ?4 is mobilized from HDs in invasive carcinomas and it translocates to the leading edge of cells where it engages F-actin and promotes migration/invasion. Elucidating the mechanism that regulates this mobilization of ?4 is essential for understanding its contribution to carcinoma biology. Also, much more needs to be learned about ?4 expression and function in human breast cancer. Indeed, a significant observation made with current funding is that ?4 expression correlates with basal-like tumors, aggressive tumors that retain features of basal epithelial cells and lack expression of ER, PR and HER2 (`triple negative'). Moreover, a `??4 gene signature' has been generated, a cluster of 90 genes whose expression correlates significantly with ?4 in human breast tumors and that is prognostic for reduced survival and tumor recurrence. A new phase in the study of ?4 and cancer will be initiated based on the hypothesis that ?4 functions in concert with multiple proteins to drive a specific type of breast tumor and that ?4 is a powerful tool for understanding the contribution of these other proteins to breast cancer. The first aim will assess the hypothesis that PKC-1-mediated phosphorylation of three serine residues (S1356, S1360, S1364) in the ?4 intracellular domain triggers the mobilization of ?4 from HDs to F-actin and enables it to function in migration and invasion, and as a signaling receptor. This aim will be accomplished by generating a transgenic `knock-in' mouse in which these serines are mutated to alanines. Wound healing, ?4 signaling, and the genesis and progression of basal-like tumors will be assessed in these mice. The second aim will define the relationship between ?4 and actin-binding proteins that are members of the ?4 signature. Specifically, the actin-bundling protein fascin will be studied because its expression correlates with basal-like tumors and its functions could facilitate tumor progression. The contribution of fascin to the progression of breast tumors will be determined, and the hypothesis that 24 regulates fascin localization in actin protrusions and that fascin is necessary for 24-dependent migration and invasion will be assessed. The hypothesis that PKC-1 regulates ?4 and fascin coordinately to drive migration and invasion will also be examined. The third aim focuses on SOX9, a transcription factor that is in the ?4 signature and the original basal-like gene cluster but whose functions in breast are unknown. The contribution of SOX9 to mammary gland development will be determined by generating a Sox9 targeted deletion in this epithelium. The involvement of SOX9 in basal-like tumors and its relationship to the ?4 signature will also be assessed. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand a highly aggressive form of breast cancer termed `basal-like' that is common among women with mutations in BRCA1 and in pre-menopausal African-American women. We have identified several basal-like genes whose expression is linked to increased tumor recurrence and decreased survival in women with breast cancer. The goals of this proposal are to understand how the proteins encoded by these genes contribute to breast cancer and how their functions are inter-related.

描述（由申请人提供）：这种更新的总体目标继续是对整合素的研究？4？6（称为“？4”），是阐明乳腺癌起源和进展涉及的机制的方法，并确定了该疾病临床管理的靶标。该整联蛋白将基底上皮细胞锚定在称为Hemidesmosomes（HDS）的惰性结构的基底膜上。由这笔赠款资助的工作中提出的一个开创性发现是：4在侵入性癌中动员HD，并转移到细胞的前缘，在该细胞的前缘，它与F-肌动蛋白接合并促进迁移/入侵。阐明调节这种动员的机制？4对于理解其对癌生物学的贡献至关重要。另外，还需要了解更多的？4在人类乳腺癌中的表达和功能。实际上，当前资金的一个重大观察结果是，“ 4表达”与基底样肿瘤，保留基础上皮细胞特征的侵袭性肿瘤以及缺乏ER，PR和HER2（“三重阴性”）的表达相关。此外，已经产生了一个“ 4个基因特征”，这是一个90个基因的簇，其表达与人类乳腺肿瘤中的表达显着相关，这对于降低存活率和肿瘤复发的预后是预后的。研究4和癌症的一个新阶段将基于以下假设：4与多种蛋白质一起驱动特定类型的乳腺肿瘤的假设，并且？4是理解这些其他蛋白质对乳腺癌的贡献的强大工具。第一个目的将评估以下假设：在？4中细胞内结构域中的三个丝氨酸残基（S1356，S1360，S1364）磷酸化（S1356，S1360，S1364）的磷酸化触发了从HDS到F-肌动蛋白的动员至F-肌动蛋白的动员，并使其在移民和入侵中的功能以及信号受体。该目标将通过产生转基因“敲入”小鼠来实现，其中这些丝氨酸被突变为丙氨酸。伤口愈合，4信号传导以及这些小鼠的基础样肿瘤的起源和进展。第二个目标将定义？4和肌动蛋白结合蛋白之间的关系，这些蛋白是？4签名的成员。具体而言，将研究肌动蛋白捆绑蛋白fascin，因为其表达与基底样肿瘤相关，其功能可以促进肿瘤的进展。 FASTIN对乳腺肿瘤进展的贡献将得到确定，并假设24调节肌动蛋白突起中的fascin定位，并且将评估Fascin对于24依赖性迁移和入侵所必需的。还将检查PKC-1调节的假设和法斯汀协调以驱动迁移和入侵的假设。第三个目标集中在Sox9上，Sox9是“ 4个特征和原始基底基因簇”中的转录因子，但其在乳房中的功能尚不清楚。 SOX9对乳腺发育的贡献将通过在该上皮中产生SOX9靶向缺失来确定。 Sox9参与基底样肿瘤及其与“ 4签名”的关系也将得到评估。 公共卫生相关性：该提案试图了解一种高度侵略性的乳腺癌形式，称为“基底型”，这在BRCA1突变和绝经前非裔美国妇女中很常见。我们已经确定了几种基础样基因，它们的表达与乳腺癌女性的肿瘤复发增加和降低的生存有关。该提案的目标是了解这些基因编码的蛋白质如何促进乳腺癌以及其功能如何相关。