Skip to main content

Advertisement

SpringerLink
Log in

CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer

  • Original Article
  • Published:
Cellular Oncology Aims and scope Submit manuscript

Abstract

Purpose

Cholinergic signals can be important modulators of cellular signaling in cancer. We recently have shown that knockdown of nicotinic acetylcholine receptor subunit alpha 5, CHRNA5, diminishes the proliferative potential of breast cancer cells. However, modulation of CHRNA5 expression in the context of estrogen signaling and its prognostic implications in breast cancer remained unexplored.

Methods

Meta-analyses of large breast cancer microarray cohorts were used to evaluate the association of CHRNA5 expression with estrogen (E2) treatment, estrogen receptor (ER) status and patient prognosis. The results were validated through RT-qPCR analyses of multiple E2 treated cell lines, CHRNA5 depleted MCF7 cells and across a breast cancer patient cDNA panel. We also calculated a predicted secondary (PS) score representing direct/indirect induction of gene expression by E2 based on a public dataset (GSE8597). Co-expression analysis was performed using a weighted gene co-expression network analysis (WGCNA) pipeline. Multiple other publicly available datasets such as CCLE, COSMIC and TCGA were also analyzed.

Results

Herein we found that CHRNA5 expression was induced by E2 in a dose- and time-dependent manner in breast cancer cell lines. ER− breast tumors exhibited higher CHRNA5 expression levels than ER+ tumors. Independent meta-analysis for survival outcome revealed that higher CHRNA5 expression was associated with a worse prognosis in untreated breast cancer patients. Furthermore, CHRNA5 and its co-expressed gene network emerged as secondarily induced targets of E2 stimulation. These targets were largely downregulated by exposure to CHRNA5 siRNA in MCF7 cells while the response of primary ESR1 targets was dependent on the direction of the PS-score. Moreover, primary and secondary target genes were uncoupled and clustered distinctly based on multiple public datasets.

Conclusion

Our findings strongly associate increased expression of CHRNA5 and its co-expression network with secondary E2 signaling and a worse prognosis in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. T. Truong, R.J. Hung, C.I. Amos, X. Wu, H. Bickeboller, A. Rosenberger, W. Sauter, T. Illig, H.E. Wichmann, A. Risch, H. Dienemann, R. Kaaks, P. Yang, R. Jiang, J.K. Wiencke, M. Wrensch, H. Hansen, K.T. Kelsey, K. Matsuo, K. Tajima, A.G. Schwartz, A. Wenzlaff, A. Seow, C. Ying, A. Staratschek-Jox, P. Nurnberg, E. Stoelben, J. Wolf, P. Lazarus, J.E. Muscat, C.J. Gallagher, S. Zienolddiny, A. Haugen, H.F. van der Heijden, L.A. Kiemeney, D. Isla, J.I. Mayordomo, T. Rafnar, K. Stefansson, Z.F. Zhang, S.C. Chang, J.H. Kim, Y.C. Hong, E.J. Duell, A.S. Andrew, F. Lejbkowicz, G. Rennert, H. Muller, H. Brenner, L. Le Marchand, S. Benhamou, C. Bouchardy, M.D. Teare, X. Xue, J. McLaughlin, G. Liu, J.D. McKay, P. Brennan, M.R. Spitz, Replication of lung cancer susceptibility loci at chromosomes 15q25, 5p15, and 6p21: a pooled analysis from the International Lung Cancer Consortium. J Natl Cancer Inst 102, 959–971 (2010). https://doi.org/10.1093/jnci/djq178

  2. F.S. Falvella, A. Galvan, E. Frullanti, M. Spinola, E. Calabro, A. Carbone, M. Incarbone, L. Santambrogio, U. Pastorino, T.A. Dragani, Transcription deregulation at the 15q25 locus in association with lung adenocarcinoma risk. Clin Cancer Res 15, 1837–1842 (2009). https://doi.org/10.1158/1078-0432.CCR-08-2107

    Article  CAS  PubMed  Google Scholar 

  3. S.S. Yoo, S.M. Lee, S.K. Do, W.K. Lee, D.S. Kim, J.Y. Park, Unmethylation of the CHRNB4 gene is an unfavorable prognostic factor in non-small cell lung cancer. Lung Cancer 86, 85–90 (2014). https://doi.org/10.1016/j.lungcan.2014.08.002

    Article  PubMed  Google Scholar 

  4. F.S. Falvella, T. Alberio, S. Noci, L. Santambrogio, M. Nosotti, M. Incarbone, U. Pastorino, M. Fasano, T.A. Dragani, Multiple isoforms and differential allelic expression of CHRNA5 in lung tissue and lung adenocarcinoma. Carcinogenesis 34, 1281–1285 (2013). https://doi.org/10.1093/carcin/bgt062

    Article  CAS  PubMed  Google Scholar 

  5. C.C. Warzecha, S. Shen, Y. Xing, R.P. Carstens, The epithelial splicing factors ESRP1 and ESRP2 positively and negatively regulate diverse types of alternative splicing events. RNA Biol 6, 546–562 (2009)

    Article  CAS  PubMed  Google Scholar 

  6. Q. Xu, T. Hamada, R. Kiyama, Y. Sakuma, Y. Wada-Kiyama, Site-specific regulation of gene expression by estrogen in the hypothalamus of adult female rats. Neurosci Lett 436, 35–39 (2008). https://doi.org/10.1016/j.neulet.2008.02.054

    Article  CAS  PubMed  Google Scholar 

  7. C.H. Lee, Y.C. Chang, C.S. Chen, S.H. Tu, Y.J. Wang, L.C. Chen, Y.J. Chang, P.L. Wei, H.W. Chang, C.H. Chang, C.S. Huang, C.H. Wu, Y.S. Ho, Crosstalk between nicotine and estrogen-induced estrogen receptor activation induces alpha9-nicotinic acetylcholine receptor expression in human breast cancer cells. Breast Cancer Res Treat 129, 331–345 (2011)

    Article  CAS  PubMed  Google Scholar 

  8. C.H. Lee, C.S. Huang, C.S. Chen, S.H. Tu, Y.J. Wang, Y.J. Chang, K.W. Tam, P.L. Wei, T.C. Cheng, J.S. Chu, L.C. Chen, C.H. Wu, Y.S. Ho, Overexpression and activation of the alpha9-nicotinic receptor during tumorigenesis in human breast epithelial cells. J Natl Cancer Inst 102, 1322–1335 (2010). https://doi.org/10.1093/jnci/djq300

    Article  CAS  PubMed  Google Scholar 

  9. S. Cingir Koker, E. Jahja, H. Shehwana, A.G. Keskus, O. Konu, Cholinergic receptor nicotinic alpha 5 (CHRNA5) RNAi is associated with cell cycle inhibition, apoptosis. DNA damage response and drug sensitivity in breast cancer PLoS One 13, e0208982 (2018). https://doi.org/10.1371/journal.pone.0208982

    Article  CAS  PubMed  Google Scholar 

  10. M.R. Meyer, E. Haas, E.R. Prossnitz, M. Barton, Non-genomic regulation of vascular cell function and growth by estrogen. Mol Cell Endocrinol 308, 9–16 (2009). https://doi.org/10.1016/j.mce.2009.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. J. Frasor, J.M. Danes, B. Komm, K.C. Chang, C.R. Lyttle, B.S. Katzenellenbogen, Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: Insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144, 4562–4574 (2003). https://doi.org/10.1210/en.2003-0567

  12. V. Bourdeau, J. Deschenes, D. Laperriere, M. Aid, J.H. White, S. Mader, Mechanisms of primary and secondary estrogen target gene regulation in breast cancer cells. Nucleic Acids Res 36, 76–93 (2008). https://doi.org/10.1093/nar/gkm945

    Article  CAS  PubMed  Google Scholar 

  13. V. Jagannathan, M. Robinson-Rechavi, Meta-analysis of estrogen response in MCF-7 distinguishes early target genes involved in signaling and cell proliferation from later target genes involved in cell cycle and DNA repair. BMC Syst Biol 5, 138 (2011). https://doi.org/10.1186/1752-0509-5-138

    Article  PubMed  PubMed Central  Google Scholar 

  14. B.K. Banin Hirata, J.M. Oda, R. Losi Guembarovski, C.B. Ariza, C.E. de Oliveira, M.A. Watanabe, Molecular markers for breast cancer: Prediction on tumor behavior. Dis Markers 2014, 513158–513112 (2014). https://doi.org/10.1155/2014/513158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. E.R. Prossnitz, M. Maggiolini, Mechanisms of estrogen signaling and gene expression via GPR30. Mol Cell Endocrinol 308, 32–38 (2009). https://doi.org/10.1016/j.mce.2009.03.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. B. Haibe-Kains, C. Desmedt, F. Piette, M. Buyse, F. Cardoso, L. Van't Veer, M. Piccart, G. Bontempi, C. Sotiriou, Comparison of prognostic gene expression signatures for breast cancer. BMC Genomics 9, 394 (2008). https://doi.org/10.1186/1471-2164-9-394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. E.K. Millar, P.H. Graham, S.A. O'Toole, C.M. McNeil, L. Browne, A.L. Morey, S. Eggleton, J. Beretov, C. Theocharous, A. Capp, E. Nasser, J.H. Kearsley, G. Delaney, G. Papadatos, C. Fox, R.L. Sutherland, Prediction of local recurrence, distant metastases, and death after breast-conserving therapy in early-stage invasive breast cancer using a five-biomarker panel. J Clin Oncol 27, 4701–4708 (2009). https://doi.org/10.1200/JCO.2008.21.7075

    Article  PubMed  Google Scholar 

  18. M.L. Salmans, F. Zhao, B. Andersen, The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: A potential drug target and biomarker. Breast Cancer Res 15, 204 (2013). https://doi.org/10.1186/bcr3408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. D.S. Oh, M.A. Troester, J. Usary, Z. Hu, X. He, C. Fan, J. Wu, L.A. Carey, C.M. Perou, Estrogen-regulated genes predict survival in hormone receptor-positive breast cancers. J Clin Oncol 24, 1656–1664 (2006). https://doi.org/10.1200/JCO.2005.03.2755

    Article  CAS  PubMed  Google Scholar 

  20. R. Kumar, A. Sharma, R.K. Tiwari, Application of microarray in breast cancer: An overview. J Pharm Bioallied Sci 4, 21–26 (2012). https://doi.org/10.4103/0975-7406.92726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. B.J. Trock, F. Leonessa, R. Clarke, Multidrug resistance in breast cancer: A meta-analysis of MDR1/gp170 expression and its possible functional significance. J Natl Cancer Inst 89, 917–931 (1997)

    Article  CAS  PubMed  Google Scholar 

  22. Y. Pawitan, J. Bjohle, L. Amler, A.L. Borg, S. Egyhazi, P. Hall, X. Han, L. Holmberg, F. Huang, S. Klaar, E.T. Liu, L. Miller, H. Nordgren, A. Ploner, K. Sandelin, P.M. Shaw, J. Smeds, L. Skoog, S. Wedren, J. Bergh, Gene expression profiling spares early breast cancer patients from adjuvant therapy: Derived and validated in two population-based cohorts. Breast Cancer Res 7, R953–R964 (2005). https://doi.org/10.1186/bcr1325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. T. Barrett, D.B. Troup, S.E. Wilhite, P. Ledoux, C. Evangelista, I.F. Kim, M. Tomashevsky, K.A. Marshall, K.H. Phillippy, P.M. Sherman, R.N. Muertter, M. Holko, O. Ayanbule, A. Yefanov, A. Soboleva, NCBI GEO: Archive for functional genomics data sets--10 years on. Nucleic Acids Res 39, D1005–D1010 (2011). https://doi.org/10.1093/nar/gkq1184

    Article  CAS  PubMed  Google Scholar 

  24. R. Edgar, M. Domrachev, A.E. Lash, Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res 30, 207–210 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. B. Gyorffy, A. Lanczky, A.C. Eklund, C. Denkert, J. Budczies, Q. Li, Z. Szallasi, An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat 123, 725–731 (2010). https://doi.org/10.1007/s10549-009-0674-9

    Article  CAS  PubMed  Google Scholar 

  26. X. Wang, D.D. Kang, K. Shen, C. Song, S. Lu, L.C. Chang, S.G. Liao, Z. Huo, S. Tang, Y. Ding, N. Kaminski, E. Sibille, Y. Lin, J. Li, G.C. Tseng, An R package suite for microarray meta-analysis in quality control, differentially expressed gene analysis and pathway enrichment detection. Bioinformatics 28, 2534–2536 (2012). https://doi.org/10.1093/bioinformatics/bts485

  27. G. Schwarzer, metacor: General package for meta-analysis (2016)

  28. E. Laliberté, metacor: Meta-analysis of correlation coefficients (2011)

  29. P. Langfelder, S. Horvath, WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008). https://doi.org/10.1186/1471-2105-9-559

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. P. Shannon, A. Markiel, O. Ozier, N.S. Baliga, J.T. Wang, D. Ramage, N. Amin, B. Schwikowski, T. Ideker, Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 13, 2498–2504 (2003). https://doi.org/10.1101/gr.1239303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. A. Franceschini, D. Szklarczyk, S. Frankild, M. Kuhn, M. Simonovic, A. Roth, J. Lin, P. Minguez, P. Bork, C. von Mering, L.J. Jensen, STRING v9.1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res. 41, D808–D815 (2013). https://doi.org/10.1093/nar/gks1094

    Article  CAS  PubMed  Google Scholar 

  32. R. Janky, A. Verfaillie, H. Imrichova, B. Van de Sande, L. Standaert, V. Christiaens, G. Hulselmans, K. Herten, M. Naval Sanchez, D. Potier, D. Svetlichnyy, Z. Kalender Atak, M. Fiers, J.C. Marine, S. Aerts, iRegulon: From a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol 10, e1003731 (2014). https://doi.org/10.1371/journal.pcbi.1003731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. W. da Huang, B.T. Sherman, R.A. Lempicki, Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4, 44–57 (2009). https://doi.org/10.1038/nprot.2008.211

  34. A.D. Rouillard, G.W. Gundersen, N.F. Fernandez, Z. Wang, C.D. Monteiro, M.G. McDermott, A. Ma'ayan, The harmonizome: A collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database (Oxford) 2016 (2016). https://doi.org/10.1093/database/baw100

  35. E. Cerami, J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, A. Jacobsen, C.J. Byrne, M.L. Heuer, E. Larsson, Y. Antipin, B. Reva, A.P. Goldberg, C. Sander, N. Schultz, The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov 2, 401–404 (2012). https://doi.org/10.1158/2159-8290.CD-12-0095

  36. M. Jia, T. Andreassen, L. Jensen, T.F. Bathen, I. Sinha, H. Gao, C. Zhao, L.A. Haldosen, Y. Cao, L. Girnita, S.A. Moestue, K. Dahlman-Wright, Estrogen receptor alpha promotes breast cancer by reprogramming choline metabolism. Cancer Res 76, 5634–5646 (2016). https://doi.org/10.1158/0008-5472.CAN-15-2910

  37. Q. Li, N.J. Birkbak, B. Gyorffy, Z. Szallasi, A.C. Eklund, Jetset: Selecting the optimal microarray probe set to represent a gene. BMC Bioinformatics 12, 474 (2011). https://doi.org/10.1186/1471-2105-12-474

  38. K.R. Coser, J. Chesnes, J. Hur, S. Ray, K.J. Isselbacher, T. Shioda, Global analysis of ligand sensitivity of estrogen inducible and suppressible genes in MCF7/BUS breast cancer cells by DNA microarray. Proc Natl Acad Sci U S A 100, 13994–13999 (2003). https://doi.org/10.1073/pnas.2235866100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. E. Guivarc'h, M. Buscato, A.L. Guihot, J. Favre, E. Vessieres, L. Grimaud, J. Wakim, N.J. Melhem, R. Zahreddine, M. Adlanmerini, Predominant role of nuclear versus membrane estrogen receptor α in arterial protection: Implications for estrogen receptor α modulation in cardiovascular prevention/safety. J Am Heart Assoc 7, e008950 (2018)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. J. Fu, L. Bian, L. Zhao, Z. Dong, X. Gao, H. Luan, Y. Sun, H. Song, Identification of genes for normalization of quantitative real-time PCR data in ovarian tissues. Acta Biochim Biophys Sin 42, 568–574 (2010)

    Article  CAS  PubMed  Google Scholar 

  41. K. Stokes, B. Alston-Mills, C. Teng, Estrogen response element and the promoter context of the human and mouse lactoferrin genes influence estrogen receptor α-mediated transactivation activity in mammary gland cells. J Mol Endocrinol 33, 315–334 (2004)

    Article  CAS  PubMed  Google Scholar 

  42. B.H. Akman, T. Can, A.E. Erson-Bensan, Estrogen-induced upregulation and 3'-UTR shortening of CDC6. Nucleic Acids Res 40, 10679–10688 (2012). https://doi.org/10.1093/nar/gks855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. H. Alotaibi, E.C. Yaman, E. Demirpençe, U.H. Tazebay, Unliganded estrogen receptor-α activates transcription of the mammary gland Na+/I− symporter gene. Biochem Biophys Res Commun 345, 1487–1496 (2006)

    Article  CAS  PubMed  Google Scholar 

  44. K.J. Livak, T.D. Schmittgen, Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods 25, 402–408 (2001)

  45. A. Bahreini, Z. Li, P. Wang, K.M. Levine, N. Tasdemir, L. Cao, H.M. Weir, S.L. Puhalla, N.E. Davidson, A.M. Stern, D. Chu, B.H. Park, A.V. Lee, S. Oesterreich, Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models. Breast Cancer Res 19, 60–60 (2017). https://doi.org/10.1186/s13058-017-0851-4

  46. D.C. Koboldt, R.S. Fulton, M.D. McLellan, H. Schmidt, J. Kalicki-Veizer, J.F. McMichael, L.L. Fulton, D.J. Dooling, L. Ding, E.R. Mardis, R.K. Wilson, A. Ally, M. Balasundaram, Y.S.N. Butterfield, R. Carlsen, C. Carter, A. Chu, E. Chuah, H.-J.E. Chun, R.J.N. Coope, N. Dhalla, R. Guin, C. Hirst, M. Hirst, R.A. Holt, D. Lee, H.I. Li, M. Mayo, R.A. Moore, A.J. Mungall, E. Pleasance, A.G. Robertson, J.E. Schein, A. Shafiei, P. Sipahimalani, J.R. Slobodan, D. Stoll, A. Tam, N. Thiessen, R.J. Varhol, N. Wye, T. Zeng, Y. Zhao, I. Birol, S.J.M. Jones, M.A. Marra, A.D. Cherniack, G. Saksena, R.C. Onofrio, N.H. Pho, S.L. Carter, S.E. Schumacher, B. Tabak, B. Hernandez, J. Gentry, H. Nguyen, A. Crenshaw, K. Ardlie, R. Beroukhim, W. Winckler, G. Getz, S.B. Gabriel, M. Meyerson, L. Chin, P.J. Park, R. Kucherlapati, K.A. Hoadley, J.T. Auman, C. Fan, Y.J. Turman, Y. Shi, L. Li, M.D. Topal, X. He, H.-H. Chao, A. Prat, G.O. Silva, M.D. Iglesia, W. Zhao, J. Usary, J.S. Berg, M. Adams, J. Booker, J. Wu, A. Gulabani, T. Bodenheimer, A.P. Hoyle, J.V. Simons, M.G. Soloway, L.E. Mose, S.R. Jefferys, S. Balu, J.S. Parker, D.N. Hayes, C.M. Perou, S. Malik, S. Mahurkar, H. Shen, D.J. Weisenberger, T. Triche Jr., P.H. Lai, M.S. Bootwalla, D.T. Maglinte, B.P. Berman, D.J. Van Den Berg, S.B. Baylin, P.W. Laird, C.J. Creighton, L.A. Donehower, G. Getz, M. Noble, D. Voet, G. Saksena, N. Gehlenborg, D. DiCara, J. Zhang, H. Zhang, C.-J. Wu, S.Y. Liu, M.S. Lawrence, L. Zou, A. Sivachenko, P. Lin, P. Stojanov, R. Jing, J. Cho, R. Sinha, R.W. Park, M.-D. Nazaire, J. Robinson, H. Thorvaldsdottir, J. Mesirov, P.J. Park, L. Chin, S. Reynolds, R.B. Kreisberg, B. Bernard, R. Bressler, T. Erkkila, J. Lin, V. Thorsson, W. Zhang, I. Shmulevich, G. Ciriello, N. Weinhold, N. Schultz, J. Gao, E. Cerami, B. Gross, A. Jacobsen, R. Sinha, B.A. Aksoy, Y. Antipin, B. Reva, R. Shen, B.S. Taylor, M. Ladanyi, C. Sander, P. Anur, P.T. Spellman, Y. Lu, W. Liu, R.R.G. Verhaak, G.B. Mills, R. Akbani, N. Zhang, B.M. Broom, T.D. Casasent, C. Wakefield, A.K. Unruh, K. Baggerly, K. Coombes, J.N. Weinstein, D. Haussler, C.C. Benz, J.M. Stuart, S.C. Benz, J. Zhu, C.C. Szeto, G.K. Scott, C. Yau, E.O. Paull, D. Carlin, C. Wong, A. Sokolov, J. Thusberg, S. Mooney, S. Ng, T.C. Goldstein, K. Ellrott, M. Grifford, C. Wilks, S. Ma, B. Craft, C. Yan, Y. Hu, D. Meerzaman, J.M. Gastier-Foster, J. Bowen, N.C. Ramirez, A.D. Black, R.E. Pyatt, P. White, E.J. Zmuda, J. Frick, T.M. Lichtenberg, R. Brookens, M.M. George, M.A. Gerken, H.A. Harper, K.M. Leraas, L.J. Wise, T.R. Tabler, C. McAllister, T. Barr, M. Hart-Kothari, K. Tarvin, C. Saller, G. Sandusky, C. Mitchell, M.V. Iacocca, J. Brown, B. Rabeno, C. Czerwinski, N. Petrelli, O. Dolzhansky, M. Abramov, O. Voronina, O. Potapova, J.R. Marks, W.M. Suchorska, D. Murawa, W. Kycler, M. Ibbs, K. Korski, A. Spychała, P. Murawa, J.J. Brzeziński, H. Perz, R. Łaźniak, M. Teresiak, H. Tatka, E. Leporowska, M. Bogusz-Czerniewicz, J. Malicki, A. Mackiewicz, M. Wiznerowicz, X. Van Le, B. Kohl, N.V. Tien, R. Thorp, N. Van Bang, H. Sussman, B.D. Phu, R. Hajek, N.P. Hung, T.V.T. Phuong, H.Q. Thang, K.Z. Khan, R. Penny, D. Mallery, E. Curley, C. Shelton, P. Yena, J.N. Ingle, F.J. Couch, W.L. Lingle, T.A. King, A.M. Gonzalez-Angulo, G.B. Mills, M.D. Dyer, S. Liu, X. Meng, M. Patangan, N. The Cancer Genome Atlas, L. Genome sequencing centres: Washington University in St, B.C.C.A. Genome characterization centres, I. Broad, Brigham, H. Women’s, S. Harvard Medical, C.H. University of North Carolina, H. University of Southern California/Johns, M. Genome data analysis: Baylor College of, B. Institute for Systems, C. Memorial Sloan-Kettering Cancer, H. Oregon, U. Science, M.D.A.C.C. The University of Texas, S.C.B.I. University of California, Nci, R. Biospecimen core resource: Nationwide Children’s Hospital Biospecimen Core, A.-I. Tissue source sites, Christiana, Cureline, C. Duke University Medical, C. The Greater Poland Cancer, Ilsbio, C. International Genomics, C. Mayo, Mskcc and M.D.A.C. Center, Comprehensive molecular portraits of human breast tumours. Nature 490, 61–70 (2012). https://doi.org/10.1038/nature11412

  47. T.J. Robinson, J.C. Liu, F. Vizeacoumar, T. Sun, N. Maclean, S.E. Egan, A.D. Schimmer, A. Datti, E. Zacksenhaus, RB1 status in triple negative breast cancer cells dictates response to radiation treatment and selective therapeutic drugs. PLoS One 8, e78641 (2013). https://doi.org/10.1371/journal.pone.0078641

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. P. Russo, A. Del Bufalo, M. Milic, G. Salinaro, M. Fini, A. Cesario, Cholinergic receptors as target for cancer therapy in a systems medicine perspective. Curr Mol Med 14, 1126–1138 (2014)

  49. J.J. Pink, V.C. Jordan, Models of estrogen receptor regulation by estrogens and antiestrogens in breast cancer cell lines. Cancer Res 56, 2321–2330 (1996)

  50. M.C. Alles, M. Gardiner-Garden, D.J. Nott, Y. Wang, J.A. Foekens, R.L. Sutherland, E.A. Musgrove, C.J. Ormandy, Meta-analysis and gene set enrichment relative to er status reveal elevated activity of MYC and E2F in the "basal" breast cancer subgroup. PLoS One 4, e4710 (2009). https://doi.org/10.1371/journal.pone.0004710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. L. Verlinden, I.V. Bempt, G. Eelen, M. Drijkoningen, I. Verlinden, K. Marchal, C. De Wolf-Peeters, M.R. Christiaens, L. Michiels, R. Bouillon, A. Verstuyf, The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor−/progesterone receptor-/HER-2- breast carcinomas. Cancer Res 67, 6574–6581 (2007). https://doi.org/10.1158/0008-5472.CAN-06-3545

    Article  CAS  PubMed  Google Scholar 

  52. C.-H. Lin, H.-H. Lee, C.-H. Kuei, H.-Y. Lin, L.-S. Lu, F.-P. Lee, J. Chang, J.-Y. Wang, K.-C. Hsu, Y.-F. Lin, Nicotinic acetylcholine receptor subunit Alpha-5 promotes radioresistance via recruiting E2F activity in oral squamous cell carcinoma. J Clin Med 8, 1454 (2019)

  53. W. Wang, L. Dong, B. Saville, S. Safe, Transcriptional activation of E2F1 gene expression by 17beta-estradiol in MCF-7 cells is regulated by NF-Y-Sp1/estrogen receptor interactions. Mol Endocrinol 13, 1373–1387 (1999). https://doi.org/10.1210/mend.13.8.0323

  54. K. Dahlman-Wright, Y. Qiao, P. Jonsson, J. Gustafsson, C. Williams, C. Zhao, Interplay between AP-1 and estrogen receptor α in regulating gene expression and proliferation networks in breast cancer cells. Carcinogenesis 33, 1684–1691 (2012). https://doi.org/10.1093/carcin/bgs223

    Article  CAS  PubMed  Google Scholar 

  55. J. Lukas, B.O. Petersen, K. Holm, J. Bartek, K. Helin, Deregulated expression of E2F family members induces S-phase entry and overcomes p16INK4A-mediated growth suppression. Mol Cell Biol 16, 1047–1057 (1996). https://doi.org/10.1128/mcb.16.3.1047

  56. H. Singhal, M.E. Greene, A.L. Zarnke, M. Laine, R. Al Abosy, Y.F. Chang, A.G. Dembo, K. Schoenfelt, R. Vadhi, X. Qiu, P. Rao, B. Santhamma, H.B. Nair, K.J. Nickisch, H.W. Long, L. Becker, M. Brown, G.L. Greene, Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling. Oncotarget 9, 4282–4300 (2018). https://doi.org/10.18632/oncotarget.21378

    Article  PubMed  Google Scholar 

  57. R. Mahadevappa, H. Neves, S.M. Yuen, Y. Bai, C.M. McCrudden, H.F. Yuen, Q. Wen, S.D. Zhang, H.F. Kwok, The prognostic significance of Cdc6 and Cdt1 in breast cancer. Sci Rep 7, 985 (2017). https://doi.org/10.1038/s41598-017-00998-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. G. Nassa, R. Tarallo, G. Giurato, M.R. De Filippo, M. Ravo, F. Rizzo, C. Stellato, C. Ambrosino, M. Baumann, N. Lietzèn, T.A. Nyman, A. Weisz, Post-transcriptional regulation of human breast cancer cell proteome by unliganded estrogen receptor β via microRNAs. Mol Cell Proteomics 13, 1076–1090 (2014). https://doi.org/10.1074/mcp.M113.030403

  59. E.V. Jensen, G. Cheng, C. Palmieri, S. Saji, S. Mäkelä, S. Van Noorden, T. Wahlström, M. Warner, R.C. Coombes, J.A. Gustafsson, Estrogen receptors and proliferation markers in primary and recurrent breast cancer. Proc Natl Acad Sci U S A 98, 15197–15202 (2001). https://doi.org/10.1073/pnas.211556298

  60. U.K. Mukhopadhyay, C.C. Oturkar, C. Adams, N. Wickramasekera, S. Bansal, R. Medisetty, A. Miller, W.M. Swetzig, L. Silwal-Pandit, A.-L. Børresen-Dale, C.J. Creighton, J.H. Park, S.D. Konduri, A. Mukhopadhyay, A. Caradori, A. Omilian, W. Bshara, B.A. Kaipparettu, G.M. Das, TP53 status as a determinant of pro- vs anti-tumorigenic effects of estrogen receptor-beta in breast cancer. J Natl Cancer Inst 111, 1202-1215 (2019). https://doi.org/10.1093/jnci/djz051

  61. S.K. Gruvberger-Saal, P.-O. Bendahl, L.H. Saal, M. Laakso, C. Hegardt, P. Edén, C. Peterson, P. Malmström, J. Isola, Å. Borg, Estrogen receptor β expression is associated with tamoxifen response in ERα-negative breast carcinoma. Clin Cancer Res 13, 1987–1994 (2007)

  62. P. O'neill, M. Davies, A. Shaaban, H. Innes, A. Torevell, D. Sibson, C. Foster, Wild-type oestrogen receptor beta (ERβ1) mRNA and protein expression in Tamoxifen-treated post-menopausal breast cancers. Br J Cancer 91, 1694–1702 (2004)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. R. Girgert, G. Emons, C. Gründker, Estrogen signaling in ERα-negative breast cancer: ERβ and GPER. Front Endocrinol 9, 781 (2018)

  64. L.-H. Hsu, N.-M. Chu, Y.-F. Lin, S.-H. Kao, G-protein coupled estrogen receptor in breast cancer. Int J Mol Sci 20, 306 (2019)

    Article  PubMed Central  Google Scholar 

  65. L. Salvatori, L. Ravenna, F. Caporuscio, L. Principessa, G. Coroniti, L. Frati, M.A. Russo, E. Petrangeli, Action of retinoic acid receptor on EGFR gene transactivation and breast cancer cell proliferation: Interplay with the estrogen receptor. Biomed Pharmacother 65, 307–312 (2011)

    Article  CAS  PubMed  Google Scholar 

  66. V.C. Jordan, R. Curpan, P.Y. Maximov, Estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators. J Natl Cancer Inst 107, djv075 (2015)

  67. F.J. Fleming, A.D. Hill, E.W. McDermott, N.J. O’Higgins, L.S. Young, Differential recruitment of coregulator proteins steroid receptor coactivator-1 and silencing mediator for retinoid and thyroid receptors to the estrogen receptor-estrogen response element by β-estradiol and 4-hydroxytamoxifen in human breast cancer. J Clin Endocrinol Metabol 89, 375–383 (2004)

  68. E.N. Lyukmanova, M.L. Bychkov, G.V. Sharonov, A.V. Efremenko, M.A. Shulepko, D.S. Kulbatskii, Z.O. Shenkarev, A.V. Feofanov, D.A. Dolgikh, M.P. Kirpichnikov, Human secreted proteins SLURP-1 and SLURP-2 control the growth of epithelial cancer cells via interactions with nicotinic acetylcholine receptors. Br J Pharmacol 175, 1973–1986 (2018). https://doi.org/10.1111/bph.14194

  69. A.R. Salem, P. Martínez Pulido, F. Sanchez, Y. Sanchez, A.J. Español, M.E. Sales, Effect of low dose metronomic therapy on MCF-7 tumor cells growth and angiogenesis. Role of muscarinic acetylcholine receptors Int Immunopharmacol 84, 106514 (2020). https://doi.org/10.1016/j.intimp.2020.106514

    Article  CAS  PubMed  Google Scholar 

  70. T.I. Terpinskaya, A.V. Osipov, T.V. Balashevich, T.L. Yanchanka, E.A. Tamashionik, V.I. Tsetlin, Y.N. Utkin, Blockers of nicotinic acetylcholine receptors delay tumor growth and increase antitumor activity of mouse splenocytes. Dokl Biochem Biophys 491, 89–92 (2020). https://doi.org/10.1134/S1607672920020143

  71. Z. Sun, J. Bao, M. Zhangsun, S. Dong, D. Zhangsun, S. Luo, αO-Conotoxin GeXIVA inhibits the growth of breast cancer cells via interaction with α9 nicotine acetylcholine receptors. Marine drugs 18, 195 (2020). https://doi.org/10.3390/md18040195

  72. S.A. Ochsner, D.L. Steffen, S.G. Hilsenbeck, E.S. Chen, C. Watkins, N.J. McKenna, GEMS (gene expression MetaSignatures), a web resource for querying meta-analysis of expression microarray datasets: 17beta-estradiol in MCF-7 cells. Cancer Res 69, 23–26 (2009). https://doi.org/10.1158/0008-5472.CAN-08-3492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. D.R. Rhodes, J. Yu, K. Shanker, N. Deshpande, R. Varambally, D. Ghosh, T. Barrette, A. Pandey, A.M. Chinnaiyan, Large-scale meta-analysis of cancer microarray data identifies common transcriptional profiles of neoplastic transformation and progression. Proc Natl Acad Sci U S A 101, 9309–9314 (2004). https://doi.org/10.1073/pnas.0401994101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. B.J. Wilson, V. Giguere, Meta-analysis of human cancer microarrays reveals GATA3 is integral to the estrogen receptor alpha pathway. Mol Cancer 7, 49 (2008). 10.1186/1476–4598-7-49

  75. D.D. Smith, P. Saetrom, O. Snove Jr., C. Lundberg, G.E. Rivas, C. Glackin, G.P. Larson, Meta-analysis of breast cancer microarray studies in conjunction with conserved cis-elements suggest patterns for coordinate regulation. BMC Bioinformatics 9, 63 (2008). https://doi.org/10.1186/1471-2105-9-63

Download references

Acknowledgments

This study was funded by a research grant from The Scientific and Technological Research Council of Turkey (to OK; TUBITAK, 111 T316). We are thankful to the Higher Education Commission (HEC), Pakistan for funding Huma Shehwana for her PhD studies. We thank TUBITAK for financial assistance to Emine Sila Ozdemir during her Master studies (Scholarship 2210-E). We also thank Can Alkan and Marzieh Eslami Rasekh for helping us with the computation power needed to process microarray files.

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Science, Bilkent University, Ankara, Turkey

    Huma Shehwana, Sila E. Ozdemir, Azer A. Acikgöz, Rumeysa Biyik-Sit, Ermira Jahja, Sahika Cingir-Koker, Gizem Olmezer, Ceren Sucularli & Ozlen Konu

  2. Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, 46000, Pakistan

    Huma Shehwana

  3. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Huma Shehwana

  4. Interdisciplinary Program in Neuroscience, Bilkent University, 06800, Ankara, Turkey

    Ayse G. Keskus, Damla Gunes & Ozlen Konu

  5. Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, North Cyprus, Turkey

    Ilgin Cagnan

  6. Department of Stem Cell Sciences, Graduate School of Health Sciences, Center for Stem Cell Research and Development, Hacettepe University, 06100, Ankara, Turkey

    Ilgin Cagnan

  7. Department of Bioinformatics, Institute of Health Sciences, Hacettepe University, 06100, Ankara, Turkey

    Ceren Sucularli

  8. UNAM-Institute of Materials Science and Nanotechnology, Bilkent University, 06800, Ankara, Turkey

    Ozlen Konu

Authors
  1. Huma Shehwana
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ayse G. Keskus
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sila E. Ozdemir
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Azer A. Acikgöz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rumeysa Biyik-Sit
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ilgin Cagnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Damla Gunes
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ermira Jahja
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sahika Cingir-Koker
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Gizem Olmezer
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ceren Sucularli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ozlen Konu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ozlen Konu.

Ethics declarations

Conflict of interest

The 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.

Supplementary Information

ESM 1

(PDF 3397 kb)

ESM 2

(PDF 151 kb)

ESM 3

(PDF 675 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shehwana, H., Keskus, A.G., Ozdemir, S.E. et al. CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer. Cell Oncol. 44, 453–472 (2021). https://doi.org/10.1007/s13402-020-00581-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13402-020-00581-x

Keywords

Search

Navigation