title: MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency.
abstract: Breast cancer is a complex disease; the molecular mechanisms involved in sporadic breast carcinogenesis remain to be elucidated. The present study aimed to explore the deficiency of breast cancer susceptibility gene 1 (BRCA1), including protein loss expression, promoter hypermethylation and gene copy deletion, its correlationship with other tumor markers expression (TP53, MYC, etc.), and clinical significance in sporadic breast cancer. BRCA1 protein expression was negative in 226 of 374 (60.4%) cases of this study. Cases negative for BRCA1 protein were more often with pathological tumor-node-metastasis stage III, positive for lymph node metastasis and MYC overexpression than BRCA1-positive tumors. BRCA1 hypermethylation was detected in 16.4% (31 of 189) breast cancers, which correlated with BRCA1 negative, ER negative, MYC overexpression, and triple-negative phenotype. In addition, the percentage of cells with BRCA1 gene copy deletion was significantly increased in BRCA1-methylated tumors. Kaplan-Meier survival analysis showed that patients with BRCA1-negative expression showed a worse overall survival (OS) than those with BRCA1-positive expression, and patients with BRCA1-methylated tumors had a significantly worse disease-free survival than did patients with unmethylated tumors. Furthermore, BRCA1 hypermethylation showed an inverse association with OS in LN-positive or p53-negative subgroup patients. Importantly, uni- and multivariate Cox regression analyses revealed that BRCA1 was an independent prognostic indicator of OS in sporadic breast cancer. Thus, we found MYC overexpression and poor prognosis in sporadic breast cancer with BRCA1 deficiency. The targeting of BRCA1 deficiency in combination with MYC-pathways inhibitors may provide a promising strategy for sporadic breast cancer care, the triple-negative subtype in particular.
authors.affiliation: Department of Pharmacology, College of Pharmaceutical Sciences, China Medical University, Shenyang, 110001, Liaoning, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.forename: Feng
authors.initials: F
authors.lastname: Jin
authors.forename: Zhaojin
authors.initials: Z
authors.lastname: Yu
authors.forename: Lin
authors.initials: L
authors.lastname: Zhao
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Bai
authors.forename: Haishan
authors.initials: H
authors.lastname: Zhao
authors.forename: Weifan
authors.initials: W
authors.lastname: Yao
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Mi
authors.forename: Enhua
authors.initials: E
authors.lastname: Wang
authors.forename: Olufunmilayo I
authors.initials: OI
authors.lastname: Olopade
authors.forename: Minjie
authors.initials: M
authors.lastname: Wei
mesh_terms: D000328:Adult; D019313:BRCA1 Protein / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D017404:In Situ Hybridization, Fluorescence / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D016016:Proportional Hazards Models; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc