SNPs near the cysteine proteinase cathepsin O gene (CTSO) determine tamoxifen sensitivity in ERα-positive breast cancer through regulation of BRCA1.

Abstract

Tamoxifen is one of the most commonly employed endocrine therapies for patients with estrogen receptor α (ERα)-positive breast cancer. Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance. We previously reported a genome-wide association study that identified common SNPs near the CTSO gene and in ZNF423 associated with development of breast cancer during tamoxifen therapy in the NSABP P-1 and P-2 breast cancer prevention trials. Here, we have investigated their roles in ERα-positive breast cancer growth and tamoxifen response, focusing on the mechanism of CTSO. We performed in vitro studies including luciferase assays, cell proliferation, and mass spectrometry-based assays using ERα-positive breast cancer cells and a panel of genomic data-rich lymphoblastoid cell lines. We report that CTSO reduces the protein levels of BRCA1 and ZNF423 through cysteine proteinase-mediated degradation. We also have identified a series of transcription factors of BRCA1 that are regulated by CTSO at the protein level. Importantly, the variant CTSO SNP genotypes are associated with increased CTSO and decreased BRCA1 protein levels that confer resistance to tamoxifen. Characterization of the effect of both CTSO SNPs and ZNF423 SNPs on tamoxifen response revealed that cells with different combinations of CTSO and ZNF423 genotypes respond differently to Tamoxifen, PARP inhibitors or the combination of the two drugs due to SNP dependent differential regulation of BRCA1 levels. Therefore, these genotypes might be biomarkers for selection of individual drug to achieve the best efficacy.

• Authors: Junmei Cairns, James N Ingle, Lawrence D Wickerham, Richard Weinshilboum, Mohan Liu, Liewei Wang
• Journal: PLoS genetics (PLoS Genet) Vol. 13 Issue 10 Pg. e1007031 (Oct 2017) ISSN: 1553-7404 [Electronic] United States
• PMID: 28968398 (Publication Type: Journal Article)

Chemical References

• BRCA1 Protein
• BRCA1 protein, human
• DNA-Binding Proteins
• Estrogen Receptor alpha
• Genetic Markers
• Proteins
• ornithine decarboxylase antizyme
• Tamoxifen
• Cathepsins
• Cysteine Proteases
• CTSO protein, human

Topics

• BRCA1 Protein (genetics, metabolism)
• Breast Neoplasms (drug therapy, genetics)
• Cathepsins (genetics)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cysteine Proteases (genetics, metabolism)
• DNA-Binding Proteins (genetics)
• Drug Resistance, Neoplasm (genetics)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Genetic Markers
• Genome-Wide Association Study
• Humans
• Polymorphism, Single Nucleotide
• Proteins
• Quantitative Trait Loci
• Tamoxifen (pharmacology)