Impact of Cyclin D1 Isoforms in Breast Cancer

细胞周期蛋白 D1 亚型对乳腺癌的影响

• 批准号: 8015349
• 负责人: Erik Knudsen
• 金额: $ 16.05万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8015349
• 关键词: Alternative Splicing; Biochemical; Biological Models; Breast; Breast Cancer Cell; Breast Cancer Treatment; Breast Carcinoma; Bypass; CCND1 gene; Cancer cell line; Cell Culture Techniques; Cell Cycle; Cell Cycle Regulation; Cessation of life; Clinical; Complement; Country; Cutaneous; Cyclin D1; Cyclins; Data; Development; Disease; Disease Outcome; Disease Progression; Distant Metastasis; Epithelial Cells; Estrogen Receptors; Etiology; Female; Genes; Genetic Polymorphism; Human; Investigation; Lead; Link; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mammary gland; Mediating; Modeling; Mus; Nuclear; Oncogenes; Oncogenic; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Primary Neoplasm; Production; Property; Protein Isoforms; Proteins; Proto-Oncogenes; Reagent; Recurrence; Regulation; Regulatory Pathway; Relative (related person); Resistance; Risk; Role; Severity of illness; Signal Transduction; Specimen; Stress; Testing; Therapeutic; United States; Variant; Woman; Xenograft Model; base; bcl-1 Genes; cancer risk; cancer therapy; cell motility; design; human disease; malignant breast neoplasm; mouse model; outcome forecast; overexpression; public health relevance; response; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Breast cancer is the most prevalent non-cutaneous malignancy, afflicting greater than one in ten women in the United States. Aberrant proliferation is a hallmark of cancer, and extensive study has demonstrated that specific cell cycle regulatory pathways are involved in the etiology, progression and treatment of breast cancer. Cyclin D1 is a proto-oncogene that is strongly implicated in breast cancer development and disease progression. Amplification of the cyclin D1 locus occurs in 10-15% of invasive breast cancer, and over expression of cyclin D1 protein is observed in approximately 50% of breast carcinomas. Cyclin D1 plays an important function in mammary tumor genesis, as mice deficient in cyclin D1 are resistant to tumor formation driven by specific oncogenes, while enforced expression of cyclin D1 can lead to mammary carcinoma. In spite of these findings, a number of important questions remain regarding the involvement of cyclin D1 in breast cancer; particularly with reference to disease severity, response to therapy and overall patient survival. It is now apparent that cyclin D1 actually exists in two isoforms, conventional cyclin D1 which has been the subject of all prior investigation in breast cancer and cyclin D1b. Cyclin D1b is produced as an alternative splicing product of the cyclin D1 gene and results in the loss of critical regulatory motifs in the C-terminus. The production of cyclin D1b is believed to be related to a common polymorphism that has been associated with enhanced cancer risk and poor clinical outcome. Importantly, we and others have found that cyclin D1b is distinct from cyclin D1 in nuclear localization, catalytic function, and oncogenic potential. These studies suggested that cyclin D1 isoforms hold unique functions that are of high- relevance to cancer. New preliminary data demonstrate that like cyclin D1, cyclin D1b protein is aberrantly expressed in a significant fraction of breast cancer cell lines and primary tumors. Cyclin D1b protein levels are controlled in a manner distinct from cyclin D1, and evade negative regulation elicited by multiple anti- proliferative signals. Critically, the pathological overproduction of specifically cyclin D1b bypasses estrogen receptor antagonists in models for ER-positive breast cancer. Furthermore, elevated cyclin D1b protein levels in primary breast cancer is associated with increased risk for distant metastasis, disease recurrence, and poor survival. In total, these finding support the hypothesis that the two cyclin D1 isoforms provide distinct activities relevant to breast cancer tumor genesis and therapeutic bypass. The following three aims are designed to test this hypothesis: PUBLIC HEALTH RELEVANCE: Breast cancer is a leading cause of female cancer death in this country. It is known that the cyclin D1 gene plays a large role in breast cancer formation and progression. Overexpression of this gene occurs in over 50% of breast cancers, and stimulates progression of the disease. Strikingly, it is know that the single cyclin D1 gene can result in the production of two different protein products, cyclin D1a and cyclin D1b. While these two protein products have some similarities, only cyclin D1a has been studied with regard to function in breast cancer. While very little is known about cyclin D1b, we have found that cyclin D1b is actually a much more potent tumor-promoting agent, can compromise therapeutic response in model systems, and is associated with poor prognosis. Given this information, it is essential to decipher the impact of cyclin D1b on breast cancer development, progression and response to therapy.

描述（由申请人提供）：乳腺癌是最常见的非皮肤恶性肿瘤，在美国，超过十分之一的妇女患有乳腺癌。异常增殖是肿瘤的标志之一，广泛的研究表明，特定的细胞周期调控途径参与了乳腺癌的病因、进展和治疗。细胞周期蛋白D1是一种原癌基因，与乳腺癌的发生和疾病进展密切相关。在10-15%的浸润性乳腺癌中发生细胞周期蛋白D1基因座扩增，并且在大约50%的乳腺癌中观察到细胞周期蛋白D1蛋白过度表达。细胞周期蛋白D1在乳腺肿瘤发生中起重要作用，因为细胞周期蛋白D1缺陷的小鼠对由特定癌基因驱动的肿瘤形成具有抗性，而细胞周期蛋白D1的增强表达可导致乳腺癌。尽管有这些发现，仍然存在一些重要的问题，关于乳腺癌中的细胞周期蛋白D1的参与，特别是关于疾病的严重程度，对治疗的反应和患者的总体生存。 现在很明显，细胞周期蛋白D1实际上存在两种亚型，传统的细胞周期蛋白D1，这是所有先前的研究对象在乳腺癌和细胞周期蛋白D1 b。细胞周期蛋白D1 b作为细胞周期蛋白D1基因的选择性剪接产物产生，并导致C-末端关键调控基序的丢失。细胞周期蛋白D1 b的产生被认为与一种常见的多态性有关，这种多态性与癌症风险增加和临床结果不良有关。重要的是，我们和其他人已经发现，细胞周期蛋白D1 b是不同的细胞周期蛋白D1的核定位，催化功能，致癌潜力。这些研究表明，细胞周期蛋白D1亚型具有与癌症高度相关的独特功能。 新的初步数据表明，像细胞周期蛋白D1，细胞周期蛋白D1 b蛋白异常表达的乳腺癌细胞系和原发性肿瘤的显着部分。细胞周期蛋白D1 b蛋白水平以不同于细胞周期蛋白D1的方式控制，并逃避由多种抗增殖信号引起的负调控。重要的是，在ER阳性乳腺癌模型中，特异性细胞周期蛋白D1 b的病理性过度产生绕过了雌激素受体拮抗剂。此外，原发性乳腺癌中细胞周期蛋白D1 b蛋白水平升高与远处转移、疾病复发和生存不良的风险增加相关。总的来说，这些发现支持这一假设，即两个细胞周期蛋白D1亚型提供不同的活动相关的乳腺癌肿瘤的发生和治疗旁路。以下三个目标旨在检验这一假设： 公共卫生相关性：乳腺癌是这个国家女性癌症死亡的主要原因。已知细胞周期蛋白D1基因在乳腺癌的形成和发展中起重要作用。该基因的过度表达发生在超过50%的乳腺癌中，并刺激疾病的进展。引人注目的是，已知单个细胞周期蛋白D1基因可以导致两种不同蛋白质产物的产生，即细胞周期蛋白D1 a和细胞周期蛋白D1 b。虽然这两种蛋白质产物有一些相似之处，但只有细胞周期蛋白D1 a在乳腺癌中的功能进行了研究。虽然对细胞周期蛋白D1 b知之甚少，但我们发现细胞周期蛋白D1 b实际上是一种更有效的肿瘤促进剂，可以损害模型系统的治疗反应，并与预后不良有关。鉴于这些信息，有必要破译细胞周期蛋白D1 b对乳腺癌的发展，进展和治疗反应的影响。