Roles of TBX3 and its Isoform, TBX3+2a, in Breast Cancer

描述（由申请人提供）： 拟议的研究解决了关于乳腺癌分子基础的一个重要问题：具有T-box DNA结合结构域的转录因子TBX 3是否与这种情况有关。TBX 3的突变导致人类尺-乳综合征（UMS），这是一种常染色体显性遗传疾病，其特征在于乳腺缺失或发育不全以及其他先天性异常。UMS中乳腺的异常发育可以部分解释为由于TBX 3功能丧失导致乳腺组织中细胞生长缓慢，表明TBX 3是正常乳腺发育所需的。由于正常的乳腺发育和肿瘤发生有几个共同的特征，因此TBX 3基因功能的改变也可能在乳腺癌的发病机制中发挥作用。我们的初步结果使TBX 3成为乳腺癌形成的有吸引力的候选者。发现TBX 3能够使小鼠胚胎成纤维细胞（MEF）永生化，并且TBX 3在许多乳腺癌细胞系中过表达。此外，TBX 3的同源物TBX 2在一些人类乳腺癌中被发现扩增。在这里，我们建议研究TBX 3在人类乳腺癌中的作用，具体目标如下： 1.采用实时荧光定量RT-PCR技术检测50例乳腺癌组织中TBX 3的表达水平和选择性剪接模式。将审查临床信息和病理报告，TBX 3表达与其他生物标志物和结局相关; 2.研究TBX 3和TBX 3 +2a在人乳腺上皮细胞（HMEC）中过表达对衰老和肿瘤发生活性的抑制作用。 3.通过建立乳腺组织中TBX 3过表达的转基因小鼠模型，研究TBX 3的致癌活性。 这里提出的实验很有可能为理解女性死亡的主要原因之一--乳腺癌的发病机制开辟一条新的途径。我们期望TBX 3和TBX 3 +2a将成为乳腺癌的生物标志物，并将在乳腺癌的诊断和治疗中具有重要的应用。本研究建立的乳腺癌动物模型为乳腺癌的研究提供了一种新的模式。通过使用动物模型和从乳房手术中获得的组织，拟议的研究旨在优化工作的临床相关性。

DESCRIPTION (provided by applicant): The proposed studies address an important question regarding the molecular basis of breast cancer: whether the transcription factor TBX3, which has a T-box DNA binding domain, is associated with this condition. Mutations of TBX3 cause Ulnar-Mammary syndrome (UMS) in humans, an autosomal dominant disorder characterized by the absence or underdevelopment of the mammary glands and other congenital anomalies. Abnormal development of the mammary glands in UMS can be partially explained by slow growth of cells in breast tissue due to loss of function of TBX3, indicating that TBX3 is required for normal breast development. Since normal breast development and oncogenesis share several features, it raises the possibility that altered TBX3 gene function may also play a role in the pathogenesis of breast cancer. Our preliminary results have made TBX3 an attractive candidate for breast cancer formation. TBX3 was found to be able to immortalize mouse embryo fibroblast cells (MEF) and TBX3 is overexpressed in many breast cancer cell lines. In addition, TBX2, a homologue of TBX3, was found amplified in some human breast cancers. Here, we propose to study the role of TBX3 in human breast cancer with following specific aims: 1. To test the hypothesis that TBX3 's expression levels and alternative splicing patterns aberrant in 50 human breast cancer tissues with real-time taqMan RT-PCR. Clinical information and pathologic reports will be reviewed and TBX3 expression correlated with other biomarkers and outcomes; 2. To study the inhibition of senescence and oncogenesis activity of TBX3 and TBX3+2a by overexpressing TBX3 in human mammary gland epithelial cells (HMEC). 3. To create a transgenic mouse model by overexpressing TBX3 in the mammary glands to study the role of TBX3 oncogenic activity. There is a high probability that the experiments proposed here will open a new avenue to understanding the pathogenesis of one of the leading causes of death in women, breast cancer. It is our expectation that TBX3 and TBX3+2a will become a breast cancer biomarker and would have a significant application for breast cancer diagnosis and treatment. The animal model created in this application could provide a new paradigm for breast cancer study. By working with both an animal model and tissue acquired from breast surgeries, the proposed research aims to optimize the clinical relevance of the work.