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

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.