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

Purpose: The characteristic expression of DNA damage response proteins in familial breast cancers with , , or non- 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 mutations; 14 with mutations, and 138 with non- mutations). The DNA response and repair markers used for immunohistochemistry analysis included BRIT1, ATM, CHEK2, , RAD51, and PARP-1. The expressions of these proteins were analyzed in mutated tumors. The association between pathologic characteristics with mutation status was also analyzed.

Results: In familial breast cancer patients, 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. mutated tumors had lower CHEK2 and higher cytoplasmic BRIT1 expression than and non- mutation tumors. -associated tumors showed higher CHEK2 and cytoplasmic RAD51 expression than those in other groups. Nuclear PARP-1 expression in -associated tumors was significantly higher than in non- mutation tumors. Moreover, we found quite a few of negative PARP-1 expression cases in 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 mutations might have distinctive expression of different DNA damage response proteins. The reduced expression of PARP-1 in Chinese mutated breast cancer patients could influence the therapeutic outcome of PARP-1 inhibitors.