Impact of Cyclin D1 Isoforms in Breast Cancer

描述（由申请人提供）：乳腺癌是最普遍的非皮肤恶性肿瘤，在美国，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，大量研究表明，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。10-15%的浸润性乳腺癌存在cyclin D1基因座扩增，约50%的乳腺癌存在cyclin D1蛋白过表达。Cyclin D1在乳腺肿瘤发生中起着重要作用，Cyclin D1缺失的小鼠对特定癌基因驱动的肿瘤形成具有抗性，而Cyclin D1的强化表达可导致乳腺癌。尽管有这些发现，关于细胞周期蛋白D1在乳腺癌中的作用仍存在一些重要的问题；特别是在疾病严重程度，对治疗的反应和总体患者生存方面。现在很明显，细胞周期蛋白D1实际上存在于两种亚型中，传统的细胞周期蛋白D1和细胞周期蛋白D1b一直是乳腺癌研究的主题。Cyclin D1b是Cyclin D1基因的另一种剪接产物，导致c端关键调控基序的缺失。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cyclin D1b在核定位、催化功能和致癌潜能方面与cyclin D1不同。这些研究表明细胞周期蛋白D1异构体具有与癌症高度相关的独特功能。新的初步数据表明，与cyclin D1一样，cyclin 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。Cyclin D1b蛋白水平的控制方式与Cyclin D1不同，并逃避多种抗增殖信号引发的负调控。关键是，在er阳性乳腺癌模型中，特异性cyclin D1b的病理性过量产生绕过雌激素受体拮抗剂。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、疾病复发和生存率低的风险增加有关。总的来说，这些发现支持了两个周期蛋白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的假设。以下三个目标旨在验证这一假设：

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: