期刊
PHARMACOGENETICS AND GENOMICS
卷 31, 期 7, 页码 155-163出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FPC.0000000000000435
关键词
estrogen; metformin; single nucleotide polymorphisms; SERM; ZNF423
资金
- Breast Cancer Research Foundation
- Nan Sawyer Breast Cancer Fund
- Eisenberg Foundation [P50CA116201, R01 GM28157]
- NIH [U10CA180868, UG1CA18967]
The study identified potential pathways, including ribosome and AMP-activated protein kinase (AMPK) signaling, regulated by ZNF423 or ZNF423 rs9940645 SNP. The findings suggest that AMPK signaling is modulated by the ZNF423 rs9940645 SNP and may affect metformin response in breast cancer, potentially serving as a biomarker for personalized metformin treatment.
Objectives We previously discovered that the single nucleotide polymorphisms (SNP) rs9940645 in the ZNF423 gene regulate ZNF423 expression and serve as a potential biomarker for response to selective estrogen receptor modulators (SERMs). Here we explored pathways involved in ZNF423-mediated SERMs response and drugs that potentially sensitize SERMs. Methods RNA sequencing and label-free quantitative proteomics were performed to identify genes and pathways that are regulated by ZNF423 and the ZNF423 SNP. Both cultured cells and mouse xenograft models with different ZNF423 SNP genotypes were used to study the cellular responses to metformin. Results We identified ribosome and AMP-activated protein kinase (AMPK) signaling as potential pathways regulated by ZNF423 or ZNF423 rs9940645 SNP. Moreover, using clustered regularly interspaced short palindromic repeats/Cas9-engineered ZR75-1 breast cancer cells with different ZNF423 SNP genotypes, striking differences in cellular responses to metformin, either alone or in the combination of tamoxifen, were observed in both cell culture and the mouse xenograft model. Conclusions We found that AMPK signaling is modulated by the ZNF423 rs9940645 SNP in estrogen and SERM-dependent fashion. The ZNF423 rs9940645 SNP affects metformin response in breast cancer and could be a potential biomarker for tailoring the metformin treatment.
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