Abstract PO-075: Dysfunction of centrosome regulation by BRCA1-containing complex increases tumor heterogeneity

Abstract

Abstract Centrosomes are the major microtubule-organizing centers in animal cells and are critical for the formation of a bipolar mitotic spindle. Alterations in centrosome number and structure often occur together and are associated with many cancers. Centrosome aberrations results in chromosome segregation errors and abnormal cell division, leading to chromosomal instability (CIN). CIN is a major source of aneuploidy, resulting in tumor heterogeneity. Centrosome aberrations are observed in the early stages of tumorigenesis and are correlated with CIN. Breast cancer gene 1 (BRCA1) is a tumor suppressor that is associated with hereditary breast and ovarian cancer. Functions of BRCA1 in DNA repair, especially homologous recombination, has been focused, whereas BRCA1 regulates centrosome together with BRCA1-associated RING domain protein (BARD1). We identified BRCA1-interacting proteins, Obg-like ATPase 1 (OLA1) and receptor for activated C kinase (RACK1). OLA1 and RACK1 directly bound to BRCA1, BARD1, and γ-tubulin and localized the centrosomes throughout the cell cycle. Overexpression of OLA1 or RACK1 caused centrosome amplification due to centriole overduplication in mammary tissue-derived cells. The number of centrioles in cells was higher in cell lines derived from mammary tissue compared to those derived from other tissues. Knockdown of RACK1 caused abnormal centrosomal localization of BRCA1 and abrogated centriole duplication. Overexpression of RACK1 increased the centrosomal localization of BRCA1. Cancer-derived variants of BRCA1, BARD1, OLA1, and RACK1 abolished or weakened their interaction and function in centrosome duplication. These data suggest that the formation of BRCA1/BARD1/OLA1/RACK1 complex is important for centrosome regulation to maintain genome stability and that dysfunction of this complex will increase tumor heterogeneity that associated with carcinogenesis and cancer progression. Citation Format: Natsuko Chiba. Dysfunction of centrosome regulation by BRCA1-containing complex increases tumor heterogeneity [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-075.