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 Significance in Breast Cancer

CHEK2 is the main intermediate in cell response to double-stranded DNA damage. This nuclear phosphoprotein plays a role in the signaling pathway of DNA repair, as well as the stability and integrity of DNA. Activation of the CHEK2 gene in response to cellular damage prevents the progression of the cell cycle to mitosis and causes cell-cycle stoppage in the G1 phase.[13,14] Through its multiple kinase activity, CHEK2 plays a major role in the regulation of the cell cycle, apoptosis, and DNA repair. In response to double-stranded DNA damage, CHEK2 is activated by ATM and ATR kinases,[15] which result in CHEK2 phosphorylation in the N-terminal, followed by kinase activity of CHEK2.[16]

CHEK2-activated monomers activate a large number of their upstream substrates, including TP53 tumor suppressor, cell division cycle 25 (CDC25)–family proteins, serine 988 of BRCA1, and checkpoints of the cell cycle, which repair damage to DNA. These CHEK2 functions in the cell cycle raise the possibility that CHEK2 dysfunction may lead to the development of BC.[17] Mutations in CHEK2 have been observed in cancers other than BC which, similar to BC, lead to impaired apoptosis and uncontrolled proliferation of cancer cells. Although these mutations occur in different parts of CHEK2 domains compared with BC mutations,[18] they lead to lack of BRCA1, BRCA2, and P53 control, which disrupts the checkpoints of the cell cycle, causing unchecked proliferation of cancer cells and the eventual resistance of those cells to chemotherapy regimens (Table 1). Studies have shown[20,23,24] that the use of chemotherapy drugs, in combination with CHEK2 inhibitors, sensitizes breast tumor cells to drugs, which halts the growth of those cells. However, it has been indicated[19] that the use of other types of drugs, including valproic acid, activates CHEK2 and ultimately leads to cell death due to DNA damage (Table 2).

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