Expression And Significance Of BRG1 And BRM In TNBC

Objective:Chromatin remodeling complex SWI/SNF Atpase subunits BRG1 and BRM play an important role in multiple tumors.Recent studies have shown that they could play different roles in different types of tumors.Triple negative breast cancer(TNBC)is a group of highly heterogeneous tumors,lacking effective targeted therapeutics,which can be divided into basal-like and non-basal-like subtypes by immunohistochemistry based on basal-like markers.Studies indicated that BRG1 or BRM may play an oncogene role in TNBC cell lines and may be associated with chemotherapy-drug sensitivity.However,few studies have examined their expression in TNBC specimens.The prognostic value of BRG1 and BRM and the relationship between their expression and clinicopathological parameters were unknown in TNBC.Therefore,this study aimed to explore the roles of BRG1 and BRM in TNBC preliminarily,and to provide a basis for the search of new therapeutic targets for TNBC.Methods:206 cases of patients who underwent surgical resection with complete clinicopathological data at the Peking Union Medical College Hospital from 2000 to 2011 diagnosed as triple negative breast cancer were collected.The follow-up period continued from the date of surgery until March 3 1,2019.Pathological sections were retrospectively analyzed and the most representative tumor areas were carefully selected based on the matched pathological slides to make tissue microarray.Immunohistochemistry based on the EnVision two-step method was used to detect the expression of basal markers(CK5/6,EGFR and CK14),BRG1 and BRM proteins in TNBC.Any of these three basal-like markers is positive,it will be diagnosed as basal-like subtype.According to BRG1 and BRM staining intensity and percentage score,TNBC cases were divided into two groups,specifically low expression groups or high expression groups.Statistical analysis was performed with SPSS 21.0 software(SPSS,Chicago,IL).The association between basal-like subtypes or BRG1 or BRM staining and clinicopathological factors(including diagnosed age,tumor size,histological subtype,histological grade,TNM stage,P53 status,lymph node metastasis,or distant metastasis)was assess by performing the chi-square test or Fisher’s exact test.Kaplan-Meier plot and log-rank test were used to analyze the prognostic value of basal-like subtypes or BRG1 or BRM expression in TNBC.Then,univariate and multivariate COX regression analyses were performed to adjust for covariates.Two-sided P-values<0.05 were considered statistically significant.Results:1.Among the 206 patients in this study,a total of 191 patients detected basal-like markers(i.e.CK5/6,EGFR,and CK14).Most of the cases were diagnose as basal-like subtypes,accounting for 78.0%(149/191)of the total cases.Compared with non-basal subtypes,TNBC patients with basal-like subtypes had higher P53 positive rate(52.3%vs.33.3%,P=0.029)and higher histological grade(74.5%vs.52.4%,P=0.006).The differences were significant.While there were no significant correlations between basal-like subtypes and other clinical parameters including age,tumor size,stage,lymph node metastasis and distant metastasis.Survival analysis showed that the overall survival time of basal-like subtypes was shorter than non-basal-like subtypes in TNBC,but the difference wasn’t statistically significant(P=0.170).Basal-like subtypes did not affect progression free survival of TNBC patients(P=0.763).2.BRG1 protein expression:the expression of BRG1 was obtained in 197 TNBC patients.The expression of BRG1 were observed high in 81.7%(161/197)and low 18.3%(36/197)of the TNBC cases.BRG1 low expression was significantly associated with distant metastases and histological type(P<0.05).Specifically,lower expression predicted distant metastases(P=0.032).Specific types of breast cancer are more likely to have lower BRG1 expression than non-specific types(P=0.003).However,there was no significant correlation between the expression of BRG1 and other clinical parameters,such like age,tumor size,P53 status,basal-like subtype,histological grade,stage and lymph node metastasis(P>0.05).Kaplan-Meier survival curves showed that high BRG1 expression was associated with favorable outcomes(overall survival[OS],P=0.018;progression free survival[PFS],P=0.031).3.BRM protein expression:among the 197 TNBC cases,the high or low expression rates of BRM were observed in 89.4%(176/197)and 10.6%(21/197)of the total,respectively.BRM expression was not associated with any clinicopathologic features of TNBC and did not significantly effect on the prognosis of TNBC patients(OS,P=0.916;PFS,P=0.733).4.Correlation between BRG1 and BRM protein expression in TNBC:there was a significant positive correlation between BRG1 expression level and BRM expression level(P=0.013).The positive rate of lymph node metastasis,the positive rate of distant metastasis and the recurrence rate of TNBC patients with both BRG1 and BRM low expression were all higher than those of BRG1 low expression alone(62.5%vs 48.5%;75.0%vs.51.5%;50%vs.39.4%).Kaplan-Meier survival curve analysis showed that the patients with concomitant low expression of BRG1 and BRM had the worst prognosis(OS,P=0.001;PFS,P=0.062).5.Univariate analysis showed that BRG1 expression,TNM stage,lymph node metastasis,and distant metastases were significantly associated with OS and PFS in TNBC patients.Furthermore,multivariate analysis confirmed that BRG1 was an independent prognostic marker for OS(HR=0.479,95%CI:0.247-0.930,P=0.030).Meanwhile,distant metastasis was an independent predictor of worse OS and PFS(P<0.001).Conclusions:Our data indicates that the clinicopathologic features of basal-like subtypes and non-basal-like subtypes in this study cohort overlap mostly.Patients with low expression of BRG1 are more likely to have distal metastasis and are associated with poor prognosis.BRG1 could thus be an important prognostic and protective biomarker for TNBC.The role of increased and decreased BRM expression alone in TNBC remains unclear.But BRM is easily concomitantly low-expressed with BRG1.The co-low-expression of BRM and BRG1 cases had worse prognosis than the BRG1 low-expression alone cases.Therefore,the decreased expression of both BRG1 and BRM may be involved in the development,infiltration and metastasis of TNBC.However,notably,according to the current data,BRG1 may be more predictive than BRM in TNBC.