LAUSR

Background Breast cancer (BC) is a multifactorial disorder in which multiple genetic and epigenetic factors changes drive tumor initiation and progression. Bromodomain-containing protein 7 (BRD7) is a member of the bromodomain-containing protein family mainly localized in the nuclear compartment of the cell. BRD7 is a transcriptional co-activator for p53 modulating histone acetylation, p53 acetylation and promoter activity in p53 target genes. Previous studies show that BRD7 is down-regulated in a number of cancer types and this may correlate with clinical outcomes. However, the potential involvement of changes in BRD7 and prognostic importance in BC are poorly understood. Purpose of the study We have investigated the expression, CpG island methylation and sub-cellular localization of BRD7 in BC cell lines and clinical cases and thereby assessed its prognostic significance by correlating with clinicopathologic features and time-dependent clinical outcomes. Materials and methods BRD7 expression was analysed by qRT-PCR and IHC in 13 BC cancer cell lines. Expression was also assessed by IHC in 50 cases of primary breast cancer and 14 paired metastatic lesions. CpG island methylation was determined quantitatively by pyrosequencing. BC cases were divided for nuclear and non-nuclear BRD7 antigen localization and then stratified for high and low BRD7 expression. The effects of BRD7 expression and BC clinical characteristics data on OS and PFS were evaluated using univariate and multivariate Cox regression analyses. Results BRD7 was expressed at levels similar to normal breast epithelium and the CpG island unmethylated in all 13 cell lines. Methylation analysis was successful in 42 FFPE BC samples collected, with 26,2% of them methylated (11/42). IHC analysis on primary tissues revealed that BDR7 is mainly localized in the nucleus (34/50: 68%). Patients with BRD7 nuclear localization (N=34) showed smaller tumors (p=0.012), a longer OS (p=0.002) and a lower relapse rate (p=0.03). Moreover, nuclear BRD7 expression is associated with wild-type TP53 (p=0.04) and unmethylated BRD7 (p=0.04), compared to the non-nuclear cases (N=16). No difference was seen in nodal status, grading, clinical stage, histological type, ER, PR, HER2 and Ki-67 expression. Patients (N=12) showing both nuclear localization and high BRD7 expression presented the smallest tumors (10/12 = 83%) and both a longer OS (p=0,005) and PFS (p=0,001). Among the 4/14 patients with nuclear localization in their primary tumors, 3 (75%) presented a diffuse or negative BRD7 in the paired metastasis. Conclusion BRD7 is a strong candidate for breast cancer tumor suppressor and prognostic biomarker. Citation Format: Cristiana Lo Nigro, Daniela Vivenza, Ornella Garrone, Rodolfo Brizio, Fiamma Mantovani, Giannino Del Sal, Marco Carlo Merlano, Tim Crook. Bromodomain-containing protein 7 (BRD7) is a candidate tumor suppressor in breast carcinoma and prognostic biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2647.