Impact of Cyclin D1 Isoforms in Breast Cancer

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：

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: