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

  • Preclinical study
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Breast Cancer Research and Treatment Aims and scope Submit manuscript

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.

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Data availability

All experimental datasets generated are available in the supplementary materials submitted with this manuscript. Any additional information is available upon reasonable request to the corresponding author.

Abbreviations

4-OH-TAM:

4-Hydroxytamoxifene

CALML3:

Calmodulin-like protein 3

CRISPR:

Clustered, regularly interspaced short palindromic repeats

DCT:

Docetaxel

E2:

17β-Estradiol

ER:

Estrogen receptor

ERE:

Estrogen response element

GO:

Gene ontology

GWAS:

Genome-wide association study

LCL:

Lymphoblastoid cell line

NSABP:

National surgical adjuvant breast and bowel project

OE:

Overexpress

PARP:

Poly(ADP-ribose) polymerase

PBK:

PDZ binding kinas

qRT-PCR:

Quantitative reverse transcription polymerase chain reaction

SERM:

Selective estrogen receptor modulator

SNP:

Single nucleotide polymorphism

TCGA:

The Cancer Genome Atlas

WT:

Wild type

VRK1:

Vaccinia-related kinase 1

ZNF423:

Zinc finger protein 423

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Acknowledgements

We would like to acknowledge Thomas Spelsberg, Ph.D. for providing the Hs578T-ERα cell line.

Funding

This work was supported by The Breast Cancer Research Foundation (BCRF-18-076) and Eisenberg Foundation. GW was supported by ChuYing Charity Foundation. JZ was supported by the Mayo Clinic Medical Scientist Training Program (T32 GM065841) and Initiative for Maximizing Student Development (R25 GM055252).

Author information

Author notes

  1. Gen Wang, Sisi Qin and Jacqueline Zayas have equally contributed to this work.

Authors and Affiliations

  1. Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People’s Republic of China

    Gen Wang & Kunwei Shen

  2. Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA

    Gen Wang, Sisi Qin, Mohan Liu, Richard M. Weinshilboum & Liewei Wang

  3. Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic School of Medicine and the Mayo Clinic Medical Scientist Training Program, Rochester, MN, USA

    Jacqueline Zayas

  4. Department of Oncology, Mayo Clinic, Rochester, MN, USA

    James N. Ingle

  5. Pharmacogenetics and Human Genetics, Genomics Research Center, AbbVie Inc., North Chicago, IL, USA

    Mohan Liu

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Contributions

GW, SQ, and JZ participated in data acquisition, data analysis, and manuscript writing. GW designed the study and drafted the manuscript. SQ generated the ZR75-1 CRISPR Cas9 genome edited cell line. ML carried out the ZNF423 and 4-OH-TAM screens. JNI provided invaluable clinical expertise and assisted in manuscript preparation. RMW conceived the study, participated in the study design, and provided guidance in data interpretation. KS provided clinical advice and helped apply for the ChuYing Charity Foundation support. LW conceived the study, participated in the study design, coordinated the study, and is responsible for all data as described. All authors approved the final manuscript.

Corresponding authors

Correspondence to Kunwei Shen or Liewei Wang.

Ethics declarations

Conflict of interest

ML is currently affiliated with AbbVie and, however, was not at the time of involvement in this study. LW and RMW are co-founders and stockholders in OneOme, LLC, a pharmacogenomic decision support company.

Ethical approval

All experiments performed in this publication comply with US laws. There were no human participants or animals used in this study.

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Electronic supplementary material

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10549_2019_5194_MOESM1_ESM.xlsx

Supplementary material 1. Online Resource 1: Table S1 Primers sequences for luciferase and ChIP assay are provided 5’ to 3’. Catalog numbers for predesigned qRT-PCR primers are also listed. (XLSX 9 KB)

10549_2019_5194_MOESM2_ESM.xlsx

Supplementary material 2. Online Resource 2: Table S2 Hs578T-ERα cells were transiently transfected with siRNA targeting each of the 368 candidate genes and an siRNA control (siControl). Gene expression was measured by by real-time quantitative reverse transcription-PCR (qRT-PCR) and normalized to housekeeping genes. There were 109 genes with at least a twofold change in gene expression upon ZNF423 knockdown; 99 downregulated and 10 upregulated genes. (XLSX 12 KB)

10549_2019_5194_MOESM3_ESM.xlsx

Supplementary material 3. Online Resource 3: Table S3 Lymphoblastoid cell lines (LCLs) overexpressing ERα with known rs9940645 genotypes were treated with vehicle control, E2, or E2 plus 4-OH-TAM. We used at least 7 different LCLs per genotype for each treatment. Gene expression of the 368 genes was measured by quantitative reverse transcription-PCR (qRT-PCR). There were 119 genes that displayed SNP-dependent expression pattern changes in the E2 plus 4-OH-TAM treatment compared to E2 alone. Eighty-two of the 119 genes had decreased expression in wild-type cells treated with 4-OH-TAM and increased expression in variant cells treated with 4-OH-TAM, which is the same direction of change that we observed previously with ZNF423 and BRCA1. (XLSX 20 KB)

10549_2019_5194_MOESM4_ESM.pptx

Supplementary material 4. Online Resource 4: Figure S1 GO Analysis was performed by inputting genes identified from the ZNF423 knockdown or 4-OH-TAM screen into the Cluego plugin of the Cytoscape software. Depicted is the GO analysis for the 4-OH-TAM screen. (A) GO terms are visualized as nodes and grouped into a network based on function (kappa score level ≥ 0.4). The size of each node represents the enrichment significance. (B-C) Each functional group (GO group) is labeled with a unique color and named using the most significant GO term within the group. Some GO terms were shared by different GO groups. (B) The pie chart illustrates the proportion by which each GO group was represented among the GO terms. Mitotic nuclear division was the most abundant GO group. (C) The significance of GO groups is shown ranked by Bonferroni-corrected p value. (PPTX 981 KB)

10549_2019_5194_MOESM5_ESM.xlsx

Supplementary material 5. Online Resource 5: Table S4 Results from gene ontology analysis of the 109 genes which had at least a twofold change in gene expression upon ZNF423 knockdown. (XLSX 20 KB)

10549_2019_5194_MOESM6_ESM.xls

Supplementary material 6. Online Resource 6: Table S5 Results from gene ontology analysis of the 119 genes that displayed SNP-dependent expression pattern changes in the E2 plus 4-OH-TAM treatment compared to E2 alone. (XLS 64 KB)

10549_2019_5194_MOESM7_ESM.xls

Supplementary material 7. Online Resource 7: Table S6 Comparison of genes within the most significant GO term from each screen. There were 7 overlapping genes from top GO terms, including VRK1 and PBK. (XLS 28 KB)

10549_2019_5194_MOESM8_ESM.pptx

Supplementary material 8. Online Resource 8: Figure S2 ZR-75-1 cells with WT or variant SNP genotype were transiently (A) knocked down with the indicated siRNA or (B) overexpressed with the indicated plasmids. Then, qRT-PCR was performed to determine the gene expression of ZNF423, VRK1, and PBK relative to control. Data shown as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001. (PPTX 359 KB)

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Wang, G., Qin, S., Zayas, J. et al. 4-Hydroxytamoxifen enhances sensitivity of estrogen receptor α-positive breast cancer to docetaxel in an estrogen and ZNF423 SNP-dependent fashion. Breast Cancer Res Treat 175, 567–578 (2019). https://doi.org/10.1007/s10549-019-05194-z

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