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: 8118447
• 负责人: Erik Knudsen
• 金额: $ 35.07万
• 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/8118447
• 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; 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; 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，美国有超过十分之一的女性患有乳腺癌。异常增殖是癌症的一个标志，广泛的研究表明特定的细胞周期调控途径参与乳腺癌的病因、进展和治疗。 Cyclin D1 是一种原癌基因，与乳腺癌的发生和疾病进展密切相关。 10-15% 的浸润性乳腺癌中出现细胞周期蛋白 D1 基因座的扩增，并且在大约 50% 的乳腺癌中观察到细胞周期蛋白 D1 蛋白的过度表达。 Cyclin D1在乳腺肿瘤发生中发挥着重要作用，因为cyclin D1缺陷的小鼠能够抵抗特定癌基因驱动的肿瘤形成，而cyclin D1的强制表达可导致乳腺癌。尽管有这些发现，但关于细胞周期蛋白 D1 与乳腺癌的关系，仍然存在许多重要问题。特别是关于疾病严重程度、治疗反应和患者总体生存率。 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（一直是乳腺癌所有先前研究的主题）和细胞周期蛋白 D1b。细胞周期蛋白 D1b 作为细胞周期蛋白 D1 基因的替代剪接产物产生，导致 C 末端关键调控基序的丢失。细胞周期蛋白 D1b 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佳有关。重要的是，我们和其他人发现细胞周期蛋白 D1b 在核定位、催化功能和致癌潜力方面与细胞周期蛋白 D1 不同。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，与细胞周期蛋白 D1 一样，细胞周期蛋白 D1b 蛋白在乳腺癌细胞系和原发性肿瘤的很大一部分中异常表达。细胞周期蛋白 D1b 蛋白水平以与细胞周期蛋白 D1 不同的方式控制，并逃避多种抗增殖信号引发的负调节。至关重要的是，在 ER 阳性乳腺癌模型中，特异性细胞周期蛋白 D1b 的病理性过量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 D1b 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，这些发现支持了以下假设：两种细胞周期蛋白 D1 亚型提供与乳腺癌肿瘤发生和治疗旁路相关的不同活性。以下三个目标旨在检验这一假设： 公共卫生相关性：乳腺癌是该国女性癌症死亡的主要原因。众所周知，cyclin D1基因在乳腺癌的形成和进展中发挥着重要作用。该基因的过度表达发生在超过 50% 的乳腺癌中，并会刺激疾病的进展。引人注目的是，众所周知，单个细胞周期蛋白 D1 基因可以导致产生两种不同的蛋白质产物：细胞周期蛋白 D1a 和细胞周期蛋白 D1b。虽然这两种蛋白质产品有一些相似之处，但只有细胞周期蛋白 D1a 在乳腺癌中的功能得到了研究。虽然人们对细胞周期蛋白 D1b 知之甚少，但我们发现细胞周期蛋白 D1b 实际上是一种更有效的肿瘤促进剂，可以损害模型系统中的治疗反应，并且与不良预后相关。鉴于这些信息，有必要破译细胞周期蛋白 D1b 对乳腺癌发生、进展和治疗反应的影响。