Dysregulation of the centrosome induced by BRCA1 deficiency contributes to tissue‐specific carcinogenesis

Abstract

Alterations in breast cancer gene 1 (BRCA1), a tumor suppressor gene, increase the risk of breast and ovarian cancers. BRCA1 forms a heterodimer with BRCA1‐associated RING domain protein 1 (BARD1) and functions in multiple cellular processes, including DNA repair and centrosome regulation. BRCA1 acts as a tumor suppressor by promoting homologous recombination (HR) repair, and alterations in BRCA1 cause HR deficiency, not only in breast and ovarian tissues but also in other tissues. The molecular mechanisms underlying BRCA1 alteration‐induced carcinogenesis remain unclear. Centrosomes are the major microtubule‐organizing centers and function in bipolar spindle formation. The regulation of centrosome number is critical for chromosome segregation in mitosis, which maintains genomic stability. BRCA1/BARD1 function in centrosome regulation together with Obg‐like ATPase (OLA1) and receptor for activating protein C kinase 1 (RACK1). Cancer‐derived variants of BRCA1, BARD1, OLA1, and RACK1 do not interact, and aberrant expression of these proteins results in abnormal centrosome duplication in mammary‐derived cells, and rarely in other cell types. RACK1 is involved in centriole duplication in the S phase by promoting polo‐like kinase 1 activation by Aurora A, which is critical for centrosome duplication. Centriole number is higher in cells derived from mammary tissues compared with in those derived from other tissues, suggesting that tissue‐specific centrosome characterization may shed light on the tissue specificity of BRCA1‐associated carcinogenesis. Here, we explored the role of the BRCA1‐containing complex in centrosome regulation and the effect of its deficiency on tissue‐specific carcinogenesis.

Dysregulation of Microtubule Nucleating Proteins in Cancer Cells

“…The ubiquitination of γ-tubulin results in its detachment from the centrosome and inhibition of microtubule nucleation. The loss of the BRCA1 protein, as occurs in many breast cancers, induces centrosome amplification and enhances the formation of large microtubule asters from centrosomes [ 48 , 104 , 105 ]. A significant role in the regulation of breast cancer centrosomes is also played by deubiquitylase BAP1 (BRCA1-associated protein-1).…”

The Role of Non-Coding RNAs in Chromosomal Instability in Cancer

“…Mechanistically, this effect was mediated through interaction of Ginir with Cep112 (Centrosomal Protein 112) and Brca1 (Breast Cancer Type 1 Susceptibility Protein) (Panda, Setia et al 2018). Brca1 is, in addition to its prominent role in the DNA damage response, involved in centrosome regulation and its dysfunction causes increases in centrosome number (Yoshino, Fang et al 2021). High levels of Ginir disrupted the interaction between Cep112 and Brca1 and downregulated their expression, consequently leading to centrosome amplification and this effect that was phenocopied by the individual knockdown of both, Cep112 and Brca1 (Panda, Setia et al 2018).…”

Moonlighting at the Poles: Non-Canonical Functions of Centrosomes

“…These observations suggest that SPBs function as docking platforms for Cdc5 to execute the adaptation response. How this is achieved is unclear, however a possible link connecting PLK, BRCA1 and centrosomes was recently proposed in human cancers ( Yoshino et al, 2021 ). In some cases, aberrant expression of the tumor suppressor gene BRCA1 in mammary tissues can dysregulate centrosome duplication and generate a higher centriole number in vivo .…”

“…How DDICA might enhance genomic stability and/or survival remains unclear to this day. On one hand, DDICA may promote the elimination of cells bearing extensive amounts of DNA damage through mitotic catastrophe, whilst contributing to DNA damage repair via local increase of DNA repair factors at the centrosomes ( Yoshino et al, 2021 ). The rationale behind this is that an increased amount of DNA repair factors at the centrosomes stemming from DDICA could constitute an extra source of DNA repair proteins available for relocation from the centrosomes to nuclear sites of DNA damage, consequently supporting nuclear DNA repair as well as DDICA processing.…”

“…This theory, however, remains to be proven and is a work in progress in the current literature. On the other hand, this process was suggested to be beneficial for cancer cells seeking a proliferative advantage in specific growth environments, as centrosome amplification in p53-deficient cancer cells can encourage chromosome mis-segregation ( Yoshino et al, 2021 ), a key promoter of genomic heterogeneity. The mitotic catastrophe phenotype resulting from DDICA, observed primarily in breast cancer cells, is intriguingly evocative of the phenotype reported in budding yeast with the adaptation-defective cdc5-16 allele.…”