Prognostic Significance of CHEK2 Mutation in Progression of Breast Cancer

Narges Ansari, MD; Saeid Shahrabi, PhD; Abbas Khosravi, PhD; Reza Shirzad, Msc; Hadi Rezaeean, Msc

Disclosures

Lab Med. 2019;50(3):e36-e41. 

In This Article

CHEK2 Y390C Mutation

CHEK2 has 3 functional domains, namely, N-terminal SQ/TQ cluster domain (SCD), central forkhead-associated (FHA) domain, and C-terminal serine/threonine-kinase domain (KD), each of which has specific functions. Y390C mutation occurs in the serine/threonine kinase domain,[26] which disrupts the kinase function of CHEK2 and prevents the phosphorylation of downstream factors in the signaling pathway.[32] In normal conditions, ATR lies upstream of CHEK2 and causes its phosphorylation. Afterward, CHEK2 phosphorylates p53, which ceases cell-cycle progress from G1 to S when the stability of DNA is damaged until the damage to DNA is repaired.[33,34] However, CHEK2 Y390C mutation in BC prevents the activation of p53 and the proliferation of cells along with lack of DNA repair, as well as accumulation of mutations in genome of cells that eventually lead to the proliferation of tumor cells and their metastasis to different parts of the body.[35] Moreover, when the somatic cells are normally divided, p53 is ubiquitinated by the Mdm2/Mdm4 complex and destroyed. However, when cellular DNA is damaged, overexpression of p53 results in its detachment from the Mdm2/Mdm4 complex, inducing apoptosis in damaged cells.[36] Despite this, Y390C mutation in breast tumor cells impairs the activation of p53, and the cells thus become resistant to apoptosis.[37] Also, CHEK2 phosphorylates E2F1 to activate it. E2F1 that is activated by Apaf1 as well as by Ink4a/Arf (activated by p53) leads to apoptosis of cells in which DNA is damaged.[38,39] Therefore, the mutation in the second kinase domain of CHEK2 inactivates E2F1 and thus prevents apoptosis of breast tumor cells[32] (Image 1). Therefore, it can be stated that given the role played by p53 in the apoptosis of tumor cells, p53 inactivation can cause resistance of breast tumor cells to drug chemotherapy.

Image 1.

Mutations in CHEk2 and their effect in proliferation and metastasis of BC. When double-stranded DNA is damaged, checkpoint kinase 2 (CHEK2) is phosphorylated, which in turn phosphorylates its downstream factors, such as P53, P21, the breast cancer gene (BRCA), and cell division cycle 25A (CDC25A). These factors cause cell-cycle arrest to repair the damaged DNA. However, the mutation in CHEK2 domains in breast cancer impairs the cell-cycle control mechanisms, leading to the resistance of breast tumor cells to apoptosis and the metastasis of those cells to other parts of the body.

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