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.
Similar content being viewed by others
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.
References
Adabor ES, Acquaah-Mensah GK, Oduro FT (2015) SAGA: a hybrid search algorithm for Bayesian network structure learning of transcriptional regulatory networks. J Biomed Inform 53:27–35
Akinyemiju T, Sakhuja S, Waterbor J, Pisu M, Altekruse SF (2018) Racial/ethnic disparities in de novo metastases sites and survival outcomes for patients with primary breast, colorectal, and prostate cancer. Cancer Med 7(4):1183–1193. https://doi.org/10.1002/cam4.1322
Alarmo EL, Kallioniemi A (2010) Bone morphogenetic proteins in breast cancer: dual role in tumourigenesis? Endocr Relat Cancer 17(2):R123–R139
Bell R, Barraclough R, Vasieva O (2017) Gene expression meta-analysis of potential metastatic breast cancer markers. Curr Mol Med 17(3):200–210
Bhagwat AS, Vakoc CR (2015) Targeting transcription factors in cancer. Trends Cancer 1(1):53–65
Bhawe K, Roy D (2018) Interplay between NRF1, E2F4 and MYC transcription factors regulating common target genes contributes to cancer development and progression. Cell Oncol. https://doi.org/10.1007/s13402-018-0395-3
Brennan DJ, Rexhepaj E, O'Brien SL, McSherry E, O'Connor DP, Fagan A, Culhane AC, Higgins DG, Jirstrom K, Millikan RC, Landberg G, Duffy MJ, Hewitt SM, Gallagher WM, Landberg G (2008) Altered cytoplasmic-to-nuclear ratio of Survivin is a prognostic indicator in breast cancer. Clin Cancer Res 14(9):2681–2689
Bryc K, Durand EY, Macpherson JM, Reich D, Mountain JL (2015) The genetic ancestry of African Americans, Latinos, and European Americans across the United States. Am J Hum Genet 96(1):37–53
Canevari RA, Marchi FA, Domingues MA, de Andrade VP, Caldeira JR, Verjovski-Almeida S et al (2016) Identification of novel biomarkers associated with poor patient outcomes in invasive breast carcinoma. Tumour Biol 37(10):13855–13870
Chen D, Li Y, Wang L, Jiao K (2015) SEMA6D expression and patient survival in breast invasive carcinoma. Int J Breast Cancer 2015:1–10
Das JK, Felty Q, Poppiti R, Jackson RM, Roy D (2018) Nuclear respiratory factor 1 acting as an oncoprotein drives estrogen-induced breast carcinogenesis. Cells. https://doi.org/10.3390/cells7120234
Davuluri RV, Grosse I, Zhang MQ (2001) Computational identification of promoters and first exons in the human genome. Nat Genet 29(4):412–417
Dey N, Barwick BG, Moreno CS, Ordanic-Kodani M, Chen Z, Oprea-Ilies G, Tang W, Catzavelos C, Kerstann KF, Sledge GW Jr, Abramovitz M, Bouzyk M, De P, Leyland-Jones BR (2013) Wnt signaling in triple-negative breast cancer is associated with metastasis. BMC Cancer 13:1–15
Ding K, Li W, Zou Z, Zou X, Wang C (2014) CCNB1 is a prognostic biomarker for ER+ breast cancer. Med Hypotheses 83(3):359–364
Falco MM, Bleda M, Carbonell-Caballero J, Dopazo J (2016) The pan-cancer pathological regulatory landscape. Sci Rep 6:1–13
Friedman N, Koller D (2003) Being Bayesian about network structure. A Bayesian approach to structure discovery in Bayesian networks. Mach Learn 50:95–125. https://doi.org/10.1023/A:1020249912095
Fushimi K, Ray P, Kar A, Wang L, Sutherland LC, Wu JY (2008) Upregulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci USA 105(41):15708–15713
Fuster-Parra P, Tauler P, Bennasar-Veny M, Ligeza A, Lopez-Gonzalez AA, Aguilo A (2016) Bayesian network modeling: a case study of an epidemiologic system analysis of cardiovascular risk. Comput Methods Programs Biomed 126:128–142
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674
Hartemink AJ (2010) Banjo. https://www.cs.duke.edu/~amink/software/Banjo/. Accessed 06 Nov 2018
Hou L, Chen M, Wang M, Cui X, Gao Y, Xing T, Li J, Deng S, Hu J, Yang H, Jiang J (2016) Systematic analyses of key genes and pathways in the development of invasive breast cancer. Gene 593(1):1–12
Kim JH, Karnovsky A, Mahavisno V, Weymouth T, Pande M, Dolinoy DC, Rozek LS, Sartor MA (2012) LRpath analysis reveals common pathways dysregulated via DNA methylation across cancer types. BMC Genomics 13(526):1–16
Ko HL, Ren EC (2012) Functional aspects of PARP1 in DNA repair and transcription. Biomolecules 2(4):524–548
Lee C, Patil S, Sartor MA (2016) RNA-enrich: a cut-off free functional enrichment testing method for RNA-seq with improved detection power. Bioinformatics 32(7):1100–1102
Liu CY, Huang TT, Huang CT, Hu MH, Wang DS, Wang WL, Tsai WC, Lee CH, Lau KY, Yang HP, Chen MH, Shiau CW, Tseng LM, Chen KF (2017) EGFR-independent Elk1/CIP2A signalling mediates apoptotic effect of an erlotinib derivative TD52 in triple-negative breast cancer cells. Eur J Cancer 72:112–123
McConnell M, Feng S, Chen W, Zhu G, Shen D, Ponnazhagan S, Deng L, Li YP (2017) Osteoclast proton pump regulator Atp6v1c1 enhances breast cancer growth by activating the mTORC1 pathway and bone metastasis by increasing V-ATPase activity. Oncotarget 8(29):47675–47690
Mignone F, Gissi C, Liuni S, Pesole G (2002) Untranslated regions of mRNAs. Genome Biol 3(3):1–10
Pettitt SJ, Lord CJ (2018) PARP inhibitors and breast cancer: highlights and hang-ups. Expert Rev Precis Med Drug Dev 3(2):83–94
Pohl SG, Brook N, Agostino M, Arfuso F, Kumar AP, Dharmarajan A (2017) Wnt signaling in triple-negative breast cancer. Oncogenesis 6(4):e310
Ramos J, Das J, Felty Q, Yoo C, Poppiti R, Murrell D, Foster PJ, Roy D (2018) NRF1 motif sequence-enriched genes involved in ER/PR -ve HER2 +ve breast cancer signaling pathways. Breast Cancer Res Treat 8:1–17
Ramos J, Felty Q, Roy D (2020) Integrated Chip-Seq and RNA-Seq data analysis coupled with bioinformatics approaches to investigate regulatory landscape of transcription modulators in breast cancer cells. Methods Mol Biol 2102:35–59. https://doi.org/10.1007/978-1-0716-0223-2_3
Ren JX, Gong Y, Ling H, Hu X, Shao ZM (2019) Racial/ethnic differences in the outcomes of patients with metastatic breast cancer: contributions of demographic, socioeconomic, tumor and metastatic characteristics. Breast Cancer Res Treat 173(1):225–237
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43(7):1–26
Roberts PJ, Bisi JE, Strum JC, Combest AJ, Darr DB, Usary JE, Sharpless NE (2012) Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst 104(6):476–487
Rojo F, Garcia-Parra J, Zazo S, Tusquets I, Ferrer-Lozano J, Menendez S, Eroles P, Chamizo C, Servitja S, Ramírez-Merino N, Lobo F, Bellosillo B, Corominas M, Yelamos J, Serrano S, Lluch A, Rovira A, Albanell A (2012) Nuclear PARP-1 protein overexpression is associated with poor overall survival in early breast cancer. Ann Oncol 23(5):1156–1164
Rouleau M, Patel A, Hendzel MJ, Kaufmann SH, Poirier GG (2010) PARP inhibition: PARP1 and beyond. Nat Rev Cancer 10(4):293–301
Sartor MA, Leikauf GD, Medvedovic M (2009) LRpath: a logistic regression approach for identifying enriched biological groups in gene expression data. Bioinformatics 25(2):211–217
Scolz M, Widlund PO, Piazza S, Bublik DR, Reber S, Peche LY, Ciani Y, Hubner N, Isokane M, Monte M, Ellenberg J, Hyman AA, Schneider C, Bird AW (2012) GTSE1 is a microtubule plus-end tracking protein that regulates EB1-dependent cell migration. PLoS ONE 7(12):1–17
Shen M, Duan WM, Wu MY, Wang WJ, Liu L, Xu MD, Zhu J, Li DM, Gui Q, Lian L, Gong FR, Chen K, Li W, Tao M (2015) Participation of autophagy in the cytotoxicity against breast cancer cells by cisplatin. Oncol Rep 34(1):359–367
Shubbar E, Kovacs A, Hajizadeh S, Parris TZ, Nemes S, Gunnarsdottir K, Einbeigi Z, Karlsson P, Helou K (2013) Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome. BMC Cancer 13:1–10
Song Y, Zhao C, Dong L, Fu M, Xue L, Huang Z, Tong T, Zhou Z, Chen A, Yang Z, Lu N, Zhan Q (2008) Overexpression of cyclin B1 in human esophageal squamous cell carcinoma cells induces tumor cell invasive growth and metastasis. Carcinogenesis 29(2):307–315
Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, Stein TI, Nudel R, Lieder I, Mazor Y, Kaplan S, Dahary D, Warshawsky D, Guan-Golan Y, Kohn A, Rappaport N, Safran M, Lancet D (2016) The GeneCards suite: from gene data mining to disease genome sequence analyses. Curr Protoc Bioinform 54:1–33
Stewart PA, Luks J, Roycik MD, Sang QX, Zhang J (2013) Differentially expressed transcripts and dysregulated signaling pathways and networks in African American breast cancer. PLoS ONE 8(12):1–13
Vequaud E, Desplanques G, Jezequel P, Juin P, Barille-Nion S (2016) Survivin contributes to DNA repair by homologous recombination in breast cancer cells. Breast Cancer Res Treat 155(1):53–63
Yeo SK, French R, Spada F, Clarkson R (2017) Opposing roles of Nfkb2 gene products p100 and p52 in the regulation of breast cancer stem cells. Breast Cancer Res Treat 162(3):465–477
Zabkiewicz C, Resaul J, Hargest R, Jiang WG, Ye L (2017) Bone morphogenetic proteins, breast cancer, and bone metastases: striking the right balance. Endocr Relat Cancer 24(10):R349–R366
Zhu Y, Tian Y, Du J, Hu Z, Yang L, Liu J, Gu L (2012) Dvl2-dependent activation of Daam1 and RhoA regulates Wnt5a-induced breast cancer cell migration. PLoS ONE 7(5):1–12
Acknowledgements
We are grateful to the United States-India Educational Foundation for a Senior US Fulbright Nehru Scholar Award to DR.
Author information
Authors and Affiliations
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
Ethics declarations
Conflict of interest
All authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-020-03320-9