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    Awarded Grants
    Characterization of Chromosomal Condensation Defects in Breast Cancer

    Scientific Abstract:
    SCIENTIFIC ABSTRACT Characterization of Chromosomal Condensation Defects in Breast Cancer Background: The mechanism behind genomic instability in breast cancer is poorly understood. This information is essential in order to understand the genotypic and phenotypic heterogeneity that occurs during the progression of the cancer. Recently, accumulating evidence has demonstrated that the mitotic machinery significantly contributes to genomic instability. Our recent research has identified a potential new type of chromosomal aberration associated with defective chromosomal condensation. This aberration appears to be specifically related to the level of genomic instability seen in cancer cells. This structure, termed Abnormally Condensed Chromosomes or ACCs, has been observed in both cancer cell lines and ATM defective cells in high rates that correlated with the degree of genomic instability. It should be noted that the PI provided the original description for this aberration that was first published in 1988 and he has continued to develop and compile data on this structure. The original description of the biomarker was generally ignored due to the unproven opinion that ACCs were slide preparation artifacts. Recently, another research group has published similar observations. It has now been demonstrated that ACCs are not artifacts and represent a new phenotype linked to cancer. Objective/Hypothesis: Abnormal chromosomal condensation structures or ACCs represents a new type of chromosomal aberration and that defective condensation is one of the contributing causes of genomic instability in breast cancer. Specific Aims: (1) To demonstrate that ACCs represent a new type of chromosomal aberration and can be used as a biomarker for breast cancer. (2) To link condensation defects to genomic instability, the relationship between the formation of ACCs, chromosomal aberrations and the progression of breast cancer will be examined. Study Design: Using various breast cancer cell lines as well as primary breast tumor specimens we propose an expanded study to confirm our preliminary findings. (1) To characterize ACCs, a systematic analysis will be performed to document the rates of inherent and induced ACCs in various breast cancer cell lines and primary tumor cultures. (2) To link condensation defects to genomic instability the following series of tasks will be performed: a) Directly link ACCs to chromosomal segregation errors using live cells. Examine the immediate effects on chromosomal segregation that follows induction of ACCs. b) Compare the inherent and induced rates of ACCs from CIN cell lines and non-CIN cell lines. c) Correlate the rates of inherent and induced ACCs and overall genomic instability using longer-term cultures as a model. d) Evaluate the molecular connection between the changes of SMC proteins and the condensation pathway. e) Examine the relationship among condensation proteins; ACCs and chromosomal aberrations will be followed to analyze ACC rates and chromosomal aberrations after knockout of the SMC or other condensation proteins. f) Compare the cell cycle profile of clones with high and low rates of ACCs. This analysis will provide the connection between ACCs and the G2-M checkpoint regulation. h) Use tumor tissues representing different stages of breast cancer to study the rates of ACCs. Potential Outcomes and Benefits of the Research: This project represents a significant novel system designed to understand the association between condensation defects, genomic instability and breast cancer. It will establish a new type of chromosomal aberration that will connect genomic instability with cancer progression. Upon the completion of this project, ACCs can be used as a new biomarker to monitor the inherent and induced genomic instability in breast cancer cells. The establishment of the association between this biomarker and progressive cancer will provide a clinical tool enabling the assessment of progression in breast tumors.

    Lay Abstract:
    LAY ABSTRACT Characterization of Chromosomal Condensation Defects in Breast Cancer A new challenge in cancer biology is the analysis of the chromosomal condensation process, which is part of the cell cycle. Traditionally, studies have primarily focused on the cell cycle stages of replication and segregation with very limited information available on the condensation stage, particularly with reference to breast cancer. There is still an absence of significant biomarkers or experimental systems that are necessary in order to monitor defects that occur during the condensation stage of mitosis in mammalian cells. It is therefore necessary to establish a new type of system that is capable of unraveling this very important aspect of the cell cycle that has significant relevance to pre-cancer states and cancer progression. The objective of this proposal is to systematically establish and validate an innovative biomarker (that the PI's lab has recently identified) that characterizes defects that occur during the condensation stage resulting in dramatically increased genomic instability promoting tumor initiation and progression. This project aims to characterize this biomarker that has been named Abnormal Chromosomal Condensation or ACCs, and can be easily detected in conventionally prepared chromosome slides of cancer cells. ACC formation will be analyzed with advanced cytogenetic methods such as SKY and FISH that have been adapted by the PI's lab to provide greater detail on condensation defects and ACCs. These techniques will then be used to study the condensation process using cancer cell lines and primary tumor samples from patients. The specific aims of this project are based on our accumulating preliminary data that strongly indicates that defective condensation is a newly identified pathway that causes genomic instability resulting in chromosomal aberrations that lead to tumor initiation and progression. This knowledge could have far reaching implications to the medical community by providing a biomarker capable of monitoring cancer cell changes and chemotherapy effects on the cell. Both of these latter uses have been tested in preliminary studies by the PI's lab with extremely promising results. It should be noted that the PI provided the original description of this structure that was first published in 1988 and he has continued to develop and compile data on this emerging biomarker. The original description of this structure was generally ignored due to the unproven opinion that ACCs were artifacts. It has now been demonstrated that ACCs are not artifacts and ACCs are now being recognized as associated with increasing genomic instability and cancer. This proposal will provide a systematic study on primary breast tumors that is part of a planned comprehensive investigation linking this biomarker to the underlying cancer precondition of genomic instability and could provide a possible breakthrough tool to the medical community. Finally, the PI has been actively involved in the development of novel technologies in the field of molecular cytogenetics and this project represents the culmination of many years of research. The significance of the project is that this biomarker may be capable of predicting breast cancer in patients as well as detail the cellular effects of chemotherapy providing a refined prognosis. All our preliminary studies indicate that the ACC biomarker is capable of this. This biomarker has reached the stage of development where a large sample is needed to provide a comprehensive systematic study on several types of cancer. Due to the prevalence of breast cancer in society and the potential impact that this biomarker represents, it is imperative that this biomarker be tested on primary breast cancer tumors.