Impact of Cyclin D1 Isoforms in Breast Cancer

描述(申请人提供)：乳腺癌是最常见的非皮肤恶性肿瘤，在美国每十名妇女中就有一人患有此病。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通路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、发展密切相关。在10-15%的浸润性乳腺癌中可见细胞周期蛋白D1基因的扩增，约50%的乳腺癌中可观察到细胞周期蛋白D1的过度表达。细胞周期蛋白D1在乳腺肿瘤的发生中起重要作用，因为细胞周期蛋白D1缺陷的小鼠对特定癌基因驱动的肿瘤形成具有抵抗力，而细胞周期蛋白D1的表达增强可导致乳腺癌。尽管有这些发现，关于细胞周期蛋白D1在乳腺癌中的参与仍然存在一些重要的问题；特别是关于疾病的严重性、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实际上以两种不同的形式存在，传统的细胞周期蛋白D1是所有乳腺癌研究的主题，而细胞周期蛋白D1b是所有先前研究的对象。细胞周期蛋白D1b是细胞周期蛋白D1基因的选择性剪接产物，导致C末端的关键调控基序缺失。细胞周期蛋白D1b的产生被认为与一种常见的多态有关，该多态与癌症风险增加和不良临床结果有关。重要的是，我们和其他人发现，细胞周期蛋白D1b在核定位、催化功能和致癌潜能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D1b一样，细胞周期蛋白D1b蛋白在相当一部分乳腺癌细胞系和原发肿瘤中异常表达。细胞周期蛋白D1b蛋白水平的控制方式与细胞周期蛋白D1b不同，可以避开多种抗增殖信号的负调控。关键是，在ER阳性乳腺癌模型中，特定细胞周期蛋白D1b的病理性过剩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蛋白水平的升高与远处转移、疾病复发和低存活率的风险增加有关。总之，这些发现支持这样的假设，即两种细胞周期蛋白D1亚型在乳腺癌的发生和治疗旁路中提供了不同的活性。以下三个目标旨在检验这一假设： 公共卫生相关性：在这个国家，乳腺癌是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。值得注意的是，单个细胞周期蛋白D1基因可以导致两种不同的蛋白质产物的产生，即细胞周期蛋白D1a和细胞周期蛋白D1b。虽然这两种蛋白产物有一些相似之处，但关于乳腺癌的功能，只有细胞周期蛋白D1a被研究过。虽然对Cyclin D1b知之甚少，但我们发现Cyclin D1b实际上是一种更有效的肿瘤促进剂，可以在模型系统中影响治疗反应，并与不良预后有关。有了这些信息，破译细胞周期蛋白D1b对乳腺癌发生、发展和治疗反应的影响是至关重要的。

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.