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Critical Importance of Protein 4.1 in Centrosome and Mitotic Spindle Aberrations in Breast Cancer Pathogenesis

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Final rept. 1 Sep 2004-31 Aug 2006

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We proposed to test the novel hypothesis that protein 4.1 is of critical importance to centrosome and mitotic spindle aberrations that directly impact aspects of breast cancer pathogenesis. We characterized 4.1R, one member of the 4.1 family, as a component of mature centrosomes, major microtubule organizing structures in interphasic cells. Mature centrosomes become poles of mitotic spindles responsible for accurate segregation of duplicated chromosomes between dividing cells. We reasoned that aberrant 4.1 expression could engender defects in functions of centrosomes, mitotic spindles and in cytokinesis. We first analyzed centrosomal distributions of 4.1R in breast cancer cell lines with normal vs. hyperamplified centrosomes. We observed that 4.1R resides at only a subset of amplified centrosomes in the malignant breast cancer cell lines. Thus the hyperamplified centrosomes are not fully mature. We next directly tested effects of downregulating 4.1R expression. We identified specific RNA duplexes which silence 4.1R RNAi. After exposing human cells to 4.1RRNAi, we characterized perturbed centrosomal functions, several classes of aberrant mitoticspindles, defects in cytokinesis and altered cell cycle progression. Thus our initial data strongly support our hypothesis. If funding can be obtained for future investigations of 4.1 in breast cancer cell lines and tissue samples, prognostic and diagnostic tests based on assessing genetic variations as well as levels of expression of this gene in individuals could be implemented. These may be as straightforward as analysis of lymphocytes isolated from patient blood samples 4.1R is expressed in lymphocytes. An understanding of the roles of 4.1 in centrosomal and spindle abnormalities characteristic of many breast cancers can also lead to identification of 4.1 or other interacting proteins as new therapeutic targets.

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  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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