SNPs near the cysteine proteinase cathepsin O gene (CTSO) determine tamoxifen sensitivity in ERα-positive breast cancer through regulation of BRCA1.
Junmei CairnsJames N IngleLawrence D WickerhamRichard WeinshilboumMohan LiuLiewei WangPublished in: PLoS genetics (2017)
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.
Keyphrases
- positive breast cancer
- estrogen receptor
- genome wide
- breast cancer cells
- breast cancer risk
- copy number
- dna methylation
- mass spectrometry
- cell proliferation
- endoplasmic reticulum
- genome wide association study
- transcription factor
- high throughput
- amino acid
- protein protein
- emergency department
- mesenchymal stem cells
- gene expression
- high density
- single cell
- atomic force microscopy
- small molecule
- gas chromatography
- cell cycle arrest