J Breast Cancer.  2018 Sep;21(3):297-305. 10.4048/jbc.2018.21.e38.

Expression of DNA Damage Response Proteins and Associations with Clinicopathologic Characteristics in Chinese Familial Breast Cancer Patients with BRCA1/2 Mutations

• Zhu X
• Tian T
• Ruan M
• Rao J
• Yang W
• Cai X
• Sun M
• Qin G
• Zhao Z
• Wu J
• Shao Z
• Shui R
• Hu Z

• KMID: 2421370
• DOI: http://doi.org/10.4048/jbc.2018.21.e38

Abstract

PURPOSE
The characteristic expression of DNA damage response proteins in familial breast cancers with BRCA1, BRCA2, or non-BRCA1/2 mutations has not been analyzed in Chinese patients. Our study aimed to assess the differential expression of microcephalin 1 (BRIT1), ATM serine/threonine kinase (ATM), checkpoint kinase 2 (CHEK2), BRCA1, RAD51 recombinase (RAD51), and poly (ADP-ribose) polymerase 1 (PARP-1) and establish the profile of Chinese familial breast cancers with different mutation status.
METHODS
We constructed five tissue microarrays from 183 familial breast cancer patients (31 with BRCA1 mutations; 14 with BRCA2 mutations, and 138 with non-BRCA1/2 mutations). The DNA response and repair markers used for immunohistochemistry analysis included BRIT1, ATM, CHEK2, BRCA1, RAD51, and PARP-1. The expressions of these proteins were analyzed in BRCA1/2 mutated tumors. The association between pathologic characteristics with BRCA1/2 mutation status was also analyzed.
RESULTS
In familial breast cancer patients, BRCA1 mutated tumors were more frequent with high nuclear grade, estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, low Ki-67, and positive CK5/6. BRCA1 mutated tumors had lower CHEK2 and higher cytoplasmic BRIT1 expression than BRCA2 and non-BRCA1/2 mutation tumors. BRCA2-associated tumors showed higher CHEK2 and cytoplasmic RAD51 expression than those in other groups. Nuclear PARP-1 expression in BRCA1/2-associated tumors was significantly higher than in non-BRCA1/2 mutation tumors. Moreover, we found quite a few of negative PARP-1 expression cases in BRCA1/2 mutated groups.
CONCLUSION
The clinicopathologic findings of BRCA1-associated Chinese familial breast cancers were similar to the results of other studies. Chinese familial breast cancer patients with BRCA1/2 mutations might have distinctive expression of different DNA damage response proteins. The reduced expression of PARP-1 in Chinese BRCA1/2 mutated breast cancer patients could influence the therapeutic outcome of PARP-1 inhibitors.

Keyword

BRCA1 genes; BRCA2 genes; Breast neoplasms; DNA repair; Poly (ADP-ribose) polymerase-1

MeSH Terms

Asian Continental Ancestry Group*
Breast Neoplasms*
Breast*
Checkpoint Kinase 2
Cytoplasm
DNA Damage*
DNA Repair
DNA*
Estrogens
Genes, BRCA1
Genes, BRCA2
Humans
Immunohistochemistry
Phosphotransferases
Rad51 Recombinase
Receptor, Epidermal Growth Factor
DNA
Estrogens
Phosphotransferases
Rad51 Recombinase
Receptor, Epidermal Growth Factor

Figure

• 

  Figure 1 Expression of different DNA damage response proteins, (immumohistochemical stain, ×10). BRCA1 negative nuclear staining (A) and positive nuclear staining (B). Microcephalin 1 negative cytoplasmic staining (C) and positive cytoplasmic staining (D). Checkpoint kinase 2 negative nuclear staining (E) and positive nuclear staining (F). RAD51 recombinase negative cytoplasmic staining (G) and positive cytoplasmic staining (H). Poly (ADP-ribose) polymerase 1 negative nuclear staining (I) and positive nuclear staining (J). ATM serine/threonine Kinase negative nuclear staining (K) and positive nuclear staining (L).

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