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    Research Grants Awarded

    Molecular Biological Studies Of DCIS Induced By Oncogenic Kinase

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Background and Objectives/Hypothesis: We will study the early progression of breast cancer induced by Aurora-A kinase. This protein is an onco-protein that is highly and frequently expressed in more than 94% of breast cancer, strongly suggesting that this kinase could be a potential therapeutic target. We will study how Aurora-A mammary tumor is initiated in DCIS, and whether these tumors can be treatable with Aurora inhibitors. We also seek to identify molecular makers that can be used for diagnosis and treatment of Aurora-A breast cancer patients. SPECIFIC AIMS: Aim 1: Identify the genetic elements involved in Aurora-A mediated cancer progression Aim 1A. Investigate the role of PTEN in Aurora-A-induced cell transformation. Aim 1B. Investigate the role of p53 and Akt in Aurora-A-induced DCIS. Aim 2: Translational study of Aurora-A induced mammary tumor using small compounds Aim 2A. Aurora-A inhibition as therapeutic strategy in MMTV-Aurora-A tumorigenesis. Aim 2B. Identify genetic elements, which affect Aurora-A associated tumorigenesis, metastasis or VX-680 and VE-465 resistance. Study Design: We generated direct evidence that Aurora-A overexpression causes cancer in mammary gland by taking advantage of the MMTV-Aurora-A transgenic mice model. These studies clearly demonstrate that tissue-specific expression in mammary epithelial cell leads to cancer development, which is accelerated on p53-mutant background resulting in genome instability. There is other evidence that SV40 T-antigen induces tumors with elevated levels of Aurora kinases. These mice are generated and available in our laboratories, placing us in the strong position to further investigate Aurora-A-mediated cancer progression. We will also use Aurora-A inhibitors, VX-680 and VE-465, which we obtained from Merck, to investigate whether Aurora-A is a therapeutic target using small compounds in xenograft system. Molecular genetic studies will be performed to identify gonome alterations that are essential for progression or suppression of Aurora-A tumor in the presence of absence of these compounds. Impact: Detailed studies of early breast carcinogenesis have been difficult until appropriate mice model were developed. Our MMTV-Aurora-A mice are useful and invaluable model system to follow the cancer development closely. Identification of factors that accelerate Aurora-A transformation may be used as molecular makers for diagnosis and treatment, which provide us with tremendous benefits to cure breast cancer.

    Lay Abstract:
    Scientific Objective and Rationale: Aurora-A kinase has been implicated in contributing to oncogenic transformation and is frequently overexpressed and amplified in many human cancers including breast cancer. It has been reported that 94% of human primary breast cancer overexpress Aurora-A, strongly suggesting that this protein plays a crucial role in mammary carcinogenesis. Aurora-A belongs to a family of mitotic serine/threonine kinases that regulates centrosome maturation, chromosome segregation, and cytokinesis. Molecular mechanism of Aurora-A mediated cell transformation is not fully understood, but uncontrolled regulation of centrosome?s turn-over is likely responsible for its ability to transform cells. Recently, overexpression of Aurora-A was shown to induce frequent cell-division failure, giving rise to tetraploid cells with amplified centrosomes, and this finding may have general implication for the mechanism by which supernumerary centrosomes arise in human tumors. In light of evidence indicating that cell cycle progression of (near-) tetraploid cells is controlled by a G1 checkpoint that depends on both p53 and the retinoblastoma protein (Rb), the upregulation of Aurora-A and the inactivation of the p53/Rb tumor suppressor pathway could cooperate to drive carcinogenesis. How excess Aurora-A causes division failure is not known, but it is plausible that defective spindle assembly may cause chromosome segregation errors and chromatin bridges may interfere with cytokinesis. Because Aurora-A is frequently overexpressed in human breast cancer and is a potentially oncogenic protein, we are interested in inhibiting its kinase activity by providing a small compound to test the hypothesis that Aurora-A?s catalytic activity is essential for breast cancer development. We have both cell culture as well as mice model system supported by MRI techniques, in which Aurora-A overexpression is targeted in mouse mammary epithelial cells that is continuously monitored in vivo by MRI. We have already started to investigate whether VX-680 and VE-465, which are Aurora inhibitors generated by Merck, are useful for tumor suppression in vivo. Finally, identification of cellular factors that are essential for the progression/malignancy of Aurora-A breast cancer will definitely provide us with molecular markers that will be used for diagnosis and treatment. These results will lead to the better and more effective therapy of breast cancer.