Comprehensive Profiling of DNA Repair Defects in Breast Cancer Identifies a Novel Class of Endocrine Therapy Resistance Drivers

Abstract

This study was undertaken to conduct a comprehensive investigation of the role of DNA damage repair (DDR) defects in poor outcome ER disease. Expression and mutational status of DDR genes in ER breast tumors were correlated with proliferative response in neoadjuvant aromatase inhibitor therapy trials (discovery dataset), with outcomes in METABRIC, TCGA, and Loi datasets (validation datasets), and in patient-derived xenografts. A causal relationship between candidate DDR genes and endocrine treatment response, and the underlying mechanism, was then tested in ER breast cancer cell lines. Correlations between loss of expression of three genes: ( < 0.001) and ( = 0.01) from the nucleotide excision repair (NER) and ( = 0.04) from the base excision repair (BER) pathways were associated with endocrine treatment resistance in discovery dataset, and subsequently validated in independent patient cohorts. Complementary mutation analysis supported associations between mutations in NER and BER genes and reduced endocrine treatment response. A causal role for , and loss in intrinsic endocrine resistance was experimentally validated in ER breast cancer cell lines, and in ER patient-derived xenograft models. Loss of , or induced endocrine treatment resistance by dysregulating G-S transition, and therefore, increased sensitivity to CDK4/6 inhibitors. A combined DDR signature score was developed that predicted poor outcome in multiple patient cohorts. This report identifies DDR defects as a new class of endocrine treatment resistance drivers and indicates new avenues for predicting efficacy of CDK4/6 inhibition in the adjuvant treatment setting. .

Identification of a 4‐mRNA metastasis‐related prognostic signature for patients with breast cancer

“…In recent years, detailed information regarding prognosis evaluation for cancer patients can be effectively provided by genome‐wide expression profiling detection . Numerous studies have evaluated the prognostic roles of array‐based gene expression signatures acquired from tumours .…”

“…In recent years, detailed information regarding prognosis evaluation for cancer patients can be effectively provided by genome-wide expression profiling detection. [14][15][16][17] Numerous studies have evaluated the prognostic roles of array-based gene expression signatures acquired from tumours. 14,18,19 Several gene signatures have also been established to distinguish the prognosis of patients beyond the BC clinicopathologic features; however, most of them are not used clinically.…”

“…[14][15][16][17] Numerous studies have evaluated the prognostic roles of array-based gene expression signatures acquired from tumours. 14,18,19 Several gene signatures have also been established to distinguish the prognosis of patients beyond the BC clinicopathologic features; however, most of them are not used clinically. 17,19,20 Thus, identifying a novel and practical gene signature to predict patients' prognosis is urgently needed and of great clinical significance.…”

NEIL2 plays a critical role in limiting inflammation and preserving genomic integrity in H. pylori-infected gastric epithelial cells

“…cDNA was synthesized using the superscript kit (Invitrogen). Quantitative PCR (qPCR) was carried out using Syber Green master mix for target genes and normalized to the housekeeping genes GAPDH or Β-actin using the ΔΔC t method [30]. Primers were designed with Roche Universal Probe Library Assay Design software.…”

“…Recently, copy number variation analysis of the COSMIC and TCGA databases has clearly shown that, among all DNA repair proteins, NEIL2 is the most affected in various cancers, and its level is generally low (25). A mutant or functional variant of NEIL2 was also reported as a risk factor for lung cancer and squamous cell carcinoma in the oral cavity (26)(27)(28)(29), and the loss of NEIL2 is associated with poor survival in patients with estrogenreceptor positive breast cancer (30).…”