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Sensitivity to differential NRF1 gene signatures contributes to breast cancer disparities

Journal of Cancer Research and Clinical Oncology volume 146, pages 2777–2815 (2020)Cite this article

Abstract

Purpose

Nuclear respiratory factor 1 (NRF1) drives estrogen-dependent breast tumorigenesis. Herein we examined the impact of NRF1 activity on the aggressiveness and disparate molecular signature of breast cancer in Black, White, Asian, and Hispanic women.

Methods

NRF1 activity by transcription factor target enrichment analysis and causal NRF1-target gene signatures by Bayesian Network Inference with Java Objects (BANJO) and Markov Chain Monte Carlo (MCMC)-based gene order were examined in The Cancer Genome Atlas (TCGA) breast cancer cohorts.

Results

We are the first to report increased NRF1 activity based on its differential effects on genome-wide transcription associated with luminal A and B, HER2+ and triple-negative (TN) molecular subtypes of breast cancer in women of different race/ethnicity. We observed disparate NRF1 motif-containing causal gene signatures unique to Black, White, Asian, and Hispanic women for luminal A breast cancer. Further gene order searches showed molecular heterogeneity of each subtype of breast cancer. Six different gene order sequences involving CDK1, HMMR, CCNB2, CCNB1, E2F1, CREB3L4, GTSE1, and LMNB1 with almost equal weight predicted the probability of luminal A breast cancer in whites. Three different gene order sequences consisting of CCNB1 and GTSE1, and CCNB1, LMNB1, CDK1 or CASP3 predicted almost 100% probability of luminal B breast cancer in whites; CCNB1 and LMNB1 or GTSE predicted 100% HER2+ breast cancer in whites. GTSE1 and TUBA1C combined together predicted 100% probability of developing TNBC in whites; NRF1, TUBA1B and BAX with EFNA4, and NRF1 and BTRC predicated 100% TNBC in blacks. High expressor NRF1 TN breast tumors showed unfavorable prognosis with a high risk of breast cancer death in white women.

Conclusion

Our findings showed how sensitivity to high NRF1 transcriptional activity coupled with its target gene signatures contribute to racial differences in luminal A and TN breast cancer subtypes. This knowledge may be useful in personalized intervention to prevent and treat this clinically challenging problem.

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Data availability

We used public datasets in this study and details of analysis used in the current study are available from the first author or corresponding author upon request.

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Acknowledgements

We are grateful to the United States-India Educational Foundation for a Senior US Fulbright Nehru Scholar Award to DR.

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Affiliations

  1. Department of Environmental Health Sciences, Florida International University, Miami, USA

    Jairo Ramos, Quentin Felty & Deodutta Roy

  2. Department of Biostatistics, Florida International University, Miami, FL, 33199, USA

    Changwon Yoo & Zhenghua Gong

  3. Department of Dietetics and Nutrition, Florida International University, Miami, FL, 33199, USA

    Juan P. Liuzzi

  4. Department of Pathology, Florida International University, Miami, FL, USA

    Robert Poppiti

  5. School of Environmental Sciences, Jawaharlal Nehru University, New Delhi, 110067, India

    Indu Shekhar Thakur

  6. Medanta Cancer Institute, Medanta—The Medicity, Gurugram, Haryana, 122001, India

    Ruchika Goel & Ashok Kumar Vaid

  7. Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, USA

    Ricardo Jorge Komotar

  8. ICMR-National Institute of Pathology, Safdarjung Hospital Campus, New Delhi, India

    Nasreen Z. Ehtesham

  9. JH Institute of Molecular Medicine, Jamia Hamdard, New Delhi, India

    Seyed E. Hasnain

Authors
  1. Jairo Ramos
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  2. Changwon Yoo
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  3. Quentin Felty
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  4. Zhenghua Gong
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  5. Juan P. Liuzzi
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  6. Robert Poppiti
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  8. Ruchika Goel
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  11. Nasreen Z. Ehtesham
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  12. Seyed E. Hasnain
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  13. Deodutta Roy
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Contributions

The study was designed, analyzed and interpreted by DR, CW, ZG and JR. JR was helped by CW, QF and DR in writing the manuscript. AKV, IST, JL, NZE, RG, RJK, RP and SEH contributed in the preparation of the final version of the manuscript.

Corresponding author

Correspondence to Deodutta Roy.

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Ramos, J., Yoo, C., Felty, Q. et al. Sensitivity to differential NRF1 gene signatures contributes to breast cancer disparities. J Cancer Res Clin Oncol 146, 2777–2815 (2020). https://doi.org/10.1007/s00432-020-03320-9

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  • DOI: https://doi.org/10.1007/s00432-020-03320-9

Keywords

  • NRF1
  • Breast cancer disparity
  • Causal NRF1 gene signatures