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 I157T Mutation

I157T mutation occurs in the FHA domain of CDK2,[40] through which CDK2 binds its downstream factors of p53 and CDC25A, leading to their phosphorylation. When DNA is damaged, CDK2 phosphorylates CDC25A to degrade it in the proteasome.[41,42] CDC25A is a cell-cycle checkpoint that activates cyclin A/E-CDK2 complex, causing the passage of the cell from the S-phase and leading to replication of cellular DNA. However, when the DNA is damaged, CDC25A is degraded, and DNA replication is prevented. However, I157T mutation of CHEK2 keeps CDC25A active in BC, leading to the replication of damaged DNA and the spread of breast tumor cells.[43]

By contrast, according to in silico analysis, it has been shown that CHEK2 cannot be used as a prognostic factor in metastasis of breast tumor cells in susceptible patients (Figure 1). Despite this, through p21 mediation, p53 causes cell-cycle arrest to correct the damage to DNA. In fact, p21 inhibits cyclin-CDK and causes cell-cycle arrest. However, I157T mutation of CHEK2 in patients with BC inhibits both the activity of p53 tumor suppressor and p21-mediated arrest of cell cycle by p53 (Image 1).[44,45] Therefore, we conclude that I157T mutation can prevent the activity p53 tumor suppressor, which leads to the proliferation of breast tumor cells that is associated with poor prognosis.

Figure 1.

Association between CHEK2 and metastasis. It is shown that checkpoint kinase 2 (CHEK2) is not a prognosis marker for prediction of metastasis.

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