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    Research Grants Awarded

    The Contribution Of The Tex14 Kinase To Chromosomal Instability And Breast Cancer

    Grant Mechanism:
    Postdoctoral Fellowships

    Scientific Abstract:
    The contribution of the Tex14 kinase to chromosomal instability and breast cancer Rationale: Chromosomal instability (CIN), a cellular phenotype associated with aberrant chromosome number in the form of aneuploidy or polyploidy is a hallmark of cancer. Aneuploidy arises from improper disjunction of sister chromatids and failure of the spindle assembly checkpoint, the conserved surveillance mechanism that ensures the fidelity of chromosome segregation spatially and temporally. On the other hand polyploidy, arises due to aberrant exit from mitosis and failure of cytokinesis. Thus, CIN seems to arise from impairment of mitotic cell division at multiple steps. Previous studies have revealed a close correlation of CIN with accumulation of further genetic defects that may initiate and accelerate tumor progression in breast. However, the mechanism by which CIN contributes to cellular transformation and development of tumors remains unclear. To better define the contribution of CIN to breast cancer it is necessary to identify genes/proteins that promote CIN when deregulated or disrupted and subsequently to determine the mechanism by which they contribute to the cancer process. We have identified Tex14 as an amplified and overexpressed gene in human breast tumors that functions as a central regulator of mitotic cell division. Tex14 has already been shown to regulate cytokinetic abscission and to associate with midbody components like MKLP1 during cytokinesis. Here we report that Tex14 is recruited to the kinetochore in a Plk1 dependent manner and regulates kinetochore maturation through recruitment of key proteins such as Mad2 and CENP-E. Specifically, our studies have shown that knockdown of Tex14 disrupts this process leading to chromosome congression defects whereas overexpression induces aberrant delay and impairment of the spindle assembly checkpoint leading to aberrant exit from mitosis. Thus, overexpression of Tex14 leads to polyploidy and aneuploidy that may contribute to breast tumorigenesis. Here we propose to utilize Tex14 as a model for understanding CIN and the role of CIN in breast cancer. Hypothesis: Tex14 is amplified and substantially overexpressed in 60% of breast tumors and cell lines. Tex14 overexpressing cells often show aberrant mitotic delay and an extensive polypolid and/or aneuploid phenotype. Furthermore, Tex14 overexpression is associated with enhanced colony formation revealing a potential role in cellular transformation. On the basis of these data we hypothesize that Tex14 is an amplified oncogene that contributes to breast cancer progression through induction of polyploidy and aneuploidy and we postulate that Tex14 is a useful model for exploring the crucial link between CIN and breast cancer. Aim & Design: We aim (1) To define how Tex14 regulates kinetochore function during mitotic cell division; (2) To establish the contribution of Tex14 to tumor formation. Aim 1 will be accomplished through a series of cell biological and molecular studies that will determine how Tex14 controls the function of known mitotic regulators in the kinetochore. Aim 2 involves characterization of the contribution of Tex14 overexpression to cellular transformation and tumor formation in a Tex14 transgenic mouse model. Breast Cancer Reduction: Tex14 appears to be a central regulator of mitosis much like the Plk1 and Aurora kinases. Overexpression of Tex14 induces polyploidy and may contribute to tumor development and progression much like these oncogenic kinases. Similarly, disruption of Tex14 function appears to induce severe ?mitotic catastrophe? and death of cancer cells. Thus, Tex14 has strong potential as a target of pharmacological agents for treatment of cancer, in much the same way that Plk1 and Aurora kinases are being targeted in combination therapy. We believe that development of a better understanding of the contribution of Tex14 to mitotic regulation and breast cancer progression is of great importance for this purpose and also for better defining the contribution of polyploidy and kinetochore disruption to CIN and breast cancer. Furthermore, the Tex14 transgenic mouse model that will be characterized in this study may prove useful as a preclinical model for breast cancer.

    Lay Abstract:
    The contribution of the Tex14 kinase to chromosomal instability and breast cancer Hypothesis & Study Design: Chromosomal instability (CIN), a cellular phenotype associated with aberrant chromosome number was found to be associated with breast cancer and further accumulation of genetic defects that then aggravate tumor growth. In fact the great majority of breast tumors (80%) exhibit chromosomal instability suggesting that this process contributes to cancer. However, it is unclear how CIN occurs and how it drives cancer development. To better define the contribution of CIN to breast cancer it is necessary to identify genes that promote CIN when deregulated or disrupted and subsequently to determine the contribution of these genes to the cancer process. One way to find new CIN genes and oncogenes is to identify regions of the genome that are amplified (extra copies) in tumors. Using this approach we have identified Tex14 as an amplified gene on chromosome 17q23 that is overexpressed in over 60% of human breast tumors. This suggests that Tex14 contributes to a large proportion of breast cancers. In addition, we have found that Tex14 is a central regulator of the process by which cell divide. As tumor cells divide more rapidly than normal cells it is important to identify and understand the genes that contribute to this process in order to block this effect. Our studies have shown that either knockdown or overexpression of Tex14 severely affects the process of mitosis (cell division). Specifically, overexpression of Tex14 results in impairment of the spindle assembly checkpoint, the surveillance mechanism for detection of problems in the process of DNA and chromosome division that occurs just prior to cell division. By disrupting this surveillance system Tex14 causes improper separation of chromosomes leading to either a complete failure of cell division and cells with too many chromosomes or cell division resulting in inappropriate numbers of chromosomes in the resulting daughter cells. This chromosome instability (CIN) is projected to contribute to tumor formation. Separate studies have shown that Tex14 causes cells to adopt many of the characteristics of a tumor cell again suggesting a role in tumor development. Based on these data we hypothesize that Tex14 is a previously undefined oncogene that plays a central role in breast tumor development. We propose Tex14 as a unique and important model for understanding CIN and how CIN contributes to breast cancer. We aim (1) To define how Tex14 regulates kinetochore function during mitotic cell division; (2) To establish the contribution of Tex14 to tumor formation. Aim 1 involves directly studying the effects of Tex14 on the surveillance system describes above using a series of cell biological and molecular studies. Aim 2 involves characterization of the contribution of Tex14 overexpression to cellular transformation and tumor formation in a Tex14 transgenic mouse model. We must demonstrate the direct role of Tex14 in cancer using this animal model before we can move forward with other studies focused on exploring the utility of this model for preclinical studies of combination therapies for breast cancer that target genomic instability. Understanding, Reduction of Breast Cancer & Importance to Patience: We believe that development of a better knowledge of the contribution of Tex14 and CIN to cell division and breast cancer will lead to identification of novel and effective therapeutic targets for breast cancer. Tex14 appears to be a central regulator of cell division much like the Plk1 and Aurora-A kinases that are being actively targeted by novel therapeutic agents developed by several pharmaceutical agents in clinical trials. Similarly to these kinases, disruption of Tex14 function appears to induce severe ?mitotic catastrophe? and death of cancer cells. Thus, Tex14 could be an excellent candidate that can work in combination with other therapies for efficient multi-targeted drug therapy. Furthermore, we will undertake a detailed evaluation of Tex14 expression in human breast tumors and premalignant lesions in order to determine the stages in tumor development and progression that are influenced by Tex14. Finally we would like to introduce biomarkers related to Tex14 overexpression in breast cancer prognostics and determination of cancer risk. While these studies are beyond the goals of the current proposal we believe that they will become possible as a result of the findings from our studies.