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    Research Grants Awarded

    Role Of TBX3 In Breast Cancer

    Study Section:
    Tumor Cell Biology V

    Scientific Abstract:
    Background TBX3 is a T-Box transcription factor. Mutations of TBX3 cause Ulnar-Mammary syndrome with the clinical feature of the absence of, or hypoplastic mammary glands. The role of TBX3 in mammary gland development is further demonstrated in a TBX3 mutant mouse model, in which ablation of TBX3 led to the absence of mammary glands. TBX3 represses expression of the p14ARF gene, an inhibitor of MDM2-mediated degradation of p53; therefore, overexpression of TBX3 reduces the stability of p53. p53 is a tumor suppressor which is often mutated in breast cancer tissue. It has been demonstrated that TBX3 is also able to immortalize mouse embryo fibroblast cells and is overexpressed in breast cancer cell lines. Recently, it was found that the serum TBX3 level is elevated in patients with breast cancer, suggesting serum TBX3 could serve as a biomarker for breast cancer. T hese data suggest that TBX3 plays a role in breast cancer formation and led us to propose that TBX3 is an oncogene for breast cancer by negatively regulating the p53 pathway. In Aim 1, we will examine whether TBX3 is overexpressed in primary breast cancer tissues using immunohistochemistry. In Aims 2, we will test whether TBX3 executes its oncogenic activity by acting on the p53-dependent pathway. We will use readily available p53 and TBX3 knockout models in our lab and first test whether p53 +/- can rescue the lethality of the TBX3 homozygous knockout ( TBX3 -/- ) mice. We will also test whether TBX3 heterozygous knockout ( TBX3 +/-) can prevent or partially prevent breast cancer formation in p53 heterozygous in BalB/c background (p53+/-). The oncogenic activity of TBX3 will be directly assessed in a transgenic animal model by overxpressing TBX3 in the mammary glands using the MMTV promoter (Aim 3). Potential outcomes : There is a high probability that the experiments proposed here will link the genes involved in early mammary gland development and tumorigenesis, and open a new avenue to understanding the pathogenesis of breast cancer by providing a mechanistic insight of TBX3. The transgenic mouse model created in this proposal could provide a very useful tool for breast cancer study including drug screening. By working with both an animal model and tissue acquired from breast cancer surgeries, the proposed research aims to optimize the clinical relevance of the work.

    Lay Abstract:
    TBX3 belongs to a family of proteins known as transcription factors that control the expression of other genes. In humans, the loss of function of TBX3 causes Ulnar Mammary Syndrome, a genetic disorder that can pass from one generation to the next. One of the major clinical features of this disorder is the absence or underdevelopment of mammary glands in affected women, indicating that TBX3 is very important for normal breast development and growth. Breast cancer is characterized by uncontrolled growth of cells in breast tissues, but shares some similarities with normal breast development and growth. In cultured cells, TBX3 reduces the stability of p53, a tumor suppressor that is often mutated in breast cancer. We have previously shown that TBX3 prevents aging of mouse cells, and we have detected a high level of TBX3 in breast cancer cell lines. A high level of the serum TBX3 was demonstrated. Thus, TBX3 is an attractive candidate as an oncogene to influence breast cancer formation. In this proposal, we will examine whether the TBX3 protein level is high in human breast cancer tissues, and whether TBX3 act in a p53-dependent or p53-independent manner using existing animal models. Finally, we will create transgenic mice expressing TBX3 at a high level in breast tissue to see whether the mice will develop breast cancer. We expect that these innovative experiments proposed here will link mammary gland development and breast cancer formation and open a new avenue to understanding the cause of breast cancer. TBX3 holds great promise as a biomarker and has a significant application for breast cancer diagnosis, and the animal model created in this proposal could provide an important reagent for breast cancer study including for drug screening. By working with both an animal model and tissue acquired from breast cancer surgeries, the proposed research aims to optimize the clinical relevance of the work.