Critical Importance of Protein 4.1 in Centrosome and Mitiotic Spindle Aberrations in Breast Cancer Pathogenesis
Annual rept. 1 Sep 2004-31 Aug 2005
CALIFORNIA UNIV BERKELEY LAWRENCE BERKELEY LAB
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Important pathological hallmarks of many breast cancers include centrosome amplification, spindle pole defects leading to aberrant chromosome segregation, altered nucleoskeletal proteins and perturbed cytokinesis. Our recent data showing that protein 4.1 is crucial for proper centrosome, spindle and nuclear assembly maintenance led us to hypothesize that protein 4.1 is involved in centrosome dynamics, fidelity of cell division and cell cycle progression. To decipher 4.1 functions in breast cancer, we studied the detailed distribution of two 4.1 family members, 4.1R and 4.lG and found that protein 4.1 R and 4.1 G localize differentially within centrosomes and spindles and behave differently during the cell cycle. In several breast cancer cell lines with normal centrosome numbers, we determined that 4.1 R localizes to one or both centrioles in randomly growing populations. By contrast, in other breast cancer cell lines with amplified centrosomes we detected 4.1 R at a subset of hyperamplified centrioles. We are currently investigating 4.1 distribution in other breast cancer cell lines and assessing changes after specific 4.1 downregulation by RNAi. Our ultimate aim is to determine if 4.1 or its binding partners could be important chemotherapeutic targets in breast cancer treatment.
- Anatomy and Physiology