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

描述(由申请人提供)： 建议的研究解决了关于乳腺癌的分子基础的一个重要问题：具有T-box DNA结合域的转录因子TBX3是否与这种情况有关。TBX3基因突变会导致人类尺侧乳腺综合征(UMS)，这是一种常染色体显性遗传病，特征是乳腺缺失或发育不全以及其他先天性异常。UMS患者乳腺发育异常的部分原因是由于TBX3功能丧失导致乳腺组织细胞生长缓慢，提示TBX3是正常乳腺发育所必需的。由于正常的乳腺发育和肿瘤发生有几个共同的特征，这增加了TBX3基因功能改变也可能在乳腺癌的发病机制中发挥作用的可能性。我们的初步结果使TBX3成为乳腺癌形成的一个有吸引力的候选者。研究发现，TBX3能够使小鼠胚胎成纤维细胞(MEF)永生化，并且在许多乳腺癌细胞系中过表达。此外，在一些人类乳腺癌中发现了与TBX3同源的TBX2基因扩增。在这里，我们建议研究TBX3在人类乳腺癌中的作用，具体目的如下： 1.应用实时荧光定量TaqMan RT-PCR法检测50例乳腺癌组织中Tbx3‘S的表达水平和剪接模式异常的假说，并复习临床和病理报告，探讨Tbx3的表达与其他生物标志物和预后的相关性； 2.研究过表达TBX3对人乳腺上皮细胞(HMEC)衰老和致癌活性的抑制作用。 3.建立乳腺组织过表达TBX3转基因小鼠模型，研究其致癌作用。 很有可能，这里提出的实验将为了解女性主要死亡原因之一--乳腺癌的发病机制开辟一条新的途径。我们预计，TBX3和TBX3+2a将成为乳腺癌的生物标志物，并在乳腺癌的诊断和治疗中有重要的应用。本应用所建立的动物模型可为乳腺癌的研究提供新的范式。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这项工作的临床相关性。

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.