4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion.

Abstract

PURPOSE:

In early stage, ERα-positive breast cancer, concurrent use of endocrine therapy and chemotherapy has not been shown to be superior to sequential use. We hypothesized that genetic biomarkers can aid in selecting patients who would benefit from chemo-endocrine therapy. Our previous studies revealed that ZNF423 is a transcription factor for BRCA1 and an intronic single nucleotide polymorphism (SNP) in ZNF423, rs9940645, determines tamoxifen response. Here, we identified mitosis-related genes that are regulated by ZNF423 which led us to investigate taxane response in a rs9940645 SNP- and tamoxifen-dependent fashion.

METHODS:

The Cancer Genome Atlas (TCGA) breast cancer dataset was used to identify genes correlated with ZNF423. Quantitative reverse transcription PCR, chromatin immunoprecipitation, and luciferase reporter assays were used to validate the gene regulation. We used CRISPR/Cas9 to engineer paired ZR-75-1 cells which differ only in ZNF423 rs9940645 SNP genotype to test SNP-dependent phenotypes including cell cycle and cell viability. We validated our findings in an additional two breast cancer cell lines, Hs578T-ERα and HCC1500.

RESULTS:

Mitosis-related genes VRK1 and PBK, which encode histone H3 kinases, were experimentally validated to be regulated by ZNF423. ZNF423 knockdown decreased VRK1 and PBK expression and activity. Additionally, ZNF423 knockdown enhanced docetaxel-induced G2/M arrest and cytotoxicity through VRK1 or PBK regulation. Lastly, cells carrying the rs9940645 variant genotype had increased G2/M arrest and decreased cell viability when treated with docetaxel in combination with estradiol and 4-OH-TAM.

CONCLUSIONS:

We identified ZNF423 regulated genes involved in the G2/M phase of the cell cycle. 4-OH-TAM sensitized ERα-positive breast cancer cells to docetaxel in a ZNF423 SNP-dependent manner. Our findings suggest that patients with rs9940645 variant genotype may benefit from concurrent tamoxifen and docetaxel. This would impact a substantial proportion of patients because this SNP has a minor allele frequency of 0.47.

• Authors: Gen Wang, Sisi Qin, Jacqueline Zayas, James N Ingle, Mohan Liu, Richard M Weinshilboum, Kunwei Shen, Liewei Wang
• Journal: Breast cancer research and treatment (Breast Cancer Res Treat) Vol. 175 Issue 3 Pg. 567-578 (Jun 2019) ISSN: 1573-7217 [Electronic] Netherlands
• PMID: 30937657 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• ESR1 protein, human
• Estrogen Receptor alpha
• Intracellular Signaling Peptides and Proteins
• Proteins
• ornithine decarboxylase antizyme
• Tamoxifen
• Docetaxel
• afimoxifene
• Estradiol
• Protein Serine-Threonine Kinases
• VRK1 protein, human
• Mitogen-Activated Protein Kinase Kinases
• PDZ-binding kinase

Topics

• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Docetaxel (pharmacology)
• Drug Synergism
• Estradiol (pharmacology)
• Estrogen Receptor alpha (genetics, metabolism)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mitogen-Activated Protein Kinase Kinases (genetics, metabolism)
• Polymorphism, Single Nucleotide
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proteins (genetics, metabolism)
• Tamoxifen (analogs & derivatives, pharmacology)