Centrosome Aberrations as Drivers of Chromosomal Instability in Breast Cancer

Abstract

Chromosomal instability (CIN), or the dynamic change in chromosome number and composition, has been observed in cancer for decades. Recently, this phenomenon has been implicated as facilitating the acquisition of cancer hallmarks and enabling the formation of aggressive disease. Hence, CIN has the potential to serve as a therapeutic target for a wide range of cancers. CIN in cancer often occurs as a result of disrupting key regulators of mitotic fidelity and faithful chromosome segregation. As a consequence of their essential roles in mitosis, dysfunctional centrosomes can induce and maintain CIN. Centrosome defects are common in breast cancer, a heterogeneous disease characterized by high CIN. These defects include amplification, structural defects, and loss of primary cilium nucleation. Recent studies have begun to illuminate the ability of centrosome aberrations to instigate genomic flux in breast cancer cells and the tumor evolution associated with aggressive disease and poor patient outcomes. Here, we review the role of CIN in breast cancer, the processes by which centrosome defects contribute to CIN in this disease, and the emerging therapeutic approaches that are being developed to capitalize upon such aberrations.

Epigenetic alterations impede epithelial-mesenchymal transition by modulating centrosome amplification and Myc/RAS axis in triple negative breast cancer cells

“…Pericentrin plays an important role in cell division because it recruits γ-TuRCs to PCM 58 . However, centrosome aberrations have been reported to induce proliferation by ignoring microtubule-dependent tissue integrity as well as centrosome aberrations and chromosome instability enhance tumorigenesis and intratumoral heterogeneity in human breast cancer 59,60 . Thus, TNBC progression is driven www.nature.com/scientificreports/ by cell proliferation and centrosome amplification through activation of EMT.…”

The progress in our understanding of CIN in breast cancer research

“…MYC overexpression also leads to CIN by delaying the mitotic process ( 14 ). Centrosomal aberrations, including centrosomal amplifications (CA), structural defects, and loss of primary ciliated nuclei, which all lead to CIN ( 15 ), are also common in breast cancer. For instance, CA has been reported in ≥75% of breast cancer cases ( 16 ).…”

“…SCIN is more likely to occur when telomere dysfunction (e.g., telomere shortening), defective DNA damage responses, replication stress, and DNA double-strand break (DSB) repair errors occur ( 4 , 7 , 11 , 15 ) ( Figure 1B ). The faulty repair of DSBs can be caused by mutations in DNA repair genes, such as BRCA1 and BRCA2 , and the activation or overexpression of oncogenes, which can lead to chromosomal translocations, duplications, and deletions ( 17 , 18 ).…”

Long non‑coding RNAs interact with RNA‑binding proteins to regulate genomic instability in cancer cells (Review)

“…On the one hand, CIN can promote tumor metastasis and recurrence, accelerate the development of multi-drug resistance in tumors, and be associated with poorer prognoses ( 28 ). On the other hand, exceedingly high levels of CIN lead to sensitivity or even death of cancer cells after exposure to cytotoxic drugs and radiotherapy ( 29 ). Both abnormal chromosome segregation during mitosis and defects in telomere function contribute to CIN; therefore, the role of lncRNA-protein binding in these processes is reviewed ( Fig.…”