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The epithelial sodium channel has a role in breast cancer cell proliferation

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

Abstract

Purpose

Breast cancer is the most common cancer affecting women worldwide with half a million associated deaths annually. Despite a huge global effort, the pathways of breast cancer progression are not fully elucidated. Ion channels have recently emerged as novel regulators of cancer cell proliferation and metastasis. The epithelial sodium channel, ENaC, made up of α, β and γ subunits is well known for its role in Na+ reabsorption in epithelia, but a number of novel roles for ENaC have been described, including potential roles in cancer. A role for ENaC in breast cancer, however, has yet to be described. Therefore, the effects of ENaC level and activity on breast cancer proliferation were investigated.

Methods

Through the publicly available SCAN-B dataset associations between αENaC mRNA expression and breast cancer subtypes, proliferation markers and epithelial–mesenchymal transition markers (EMT) were assessed. αENaC expression, through overexpression or siRNA-mediated knockdown, and activity, through the ENaC-specific inhibitor amiloride, were altered in MCF7, T47D, BT549, and MDAMB231 breast cancer cells. MTT and EdU cell proliferation assays were used to determine the effect of these manipulations on breast cancer cell proliferation.

Results

High αENaC mRNA expression was associated with less aggressive and less proliferative breast cancer subtypes and with reduced expression of proliferation markers. Decreased αENaC expression or activity, in the mesenchymal breast cancer cell lines BT549 and MDAMB231, increased breast cancer cell proliferation. Conversely, increased αENaC expression decreased breast cancer cell proliferation.

Conclusion

αENaC expression is associated with a poor prognosis in breast cancer and is a novel regulator of breast cancer cell proliferation. Taken together, these results identify ENaC as a potential future therapeutic target.

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Data availability

Gene expression analysis was performed using data from the publicly available SCAN-B dataset.

Abbreviations

BH:

Benjamini–Hochberg correction

CDH1:

E-Cadherin

BSA:

Bovine serum albumin

EMT:

Epithelial–mesenchymal transition

ENaC:

Epithelial sodium channel

ER:

Estrogen receptor

FPKM:

Fragments per kilobase per million reads

HER2:

Human epidermal growth factor receptor 2

MCM2:

Minichromosome maintenance complex component 2

MKI67:

Antigen KI67

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

OMNI:

Otago Micro and Nanoscale Imaging Unit

PCNA:

Proliferating cell nuclear antigen

PR:

Progesterone receptor

TNBC:

Triple-negative breast cancers

VIM:

Vimentin

WMW:

Wilcoxon–Mann–Whitney

ZEB1:

Zinc finger E-box-binding homeobox 1

References

  1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M et al (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386

    CAS  PubMed  Google Scholar 

  2. Ghoncheh M, Pournamdar Z, Salehiniya H (2016) Incidence and mortality and epidemiology of breast cancer in the world. Asian Pac J Cancer Prev 17(S3):43–46

    PubMed  Google Scholar 

  3. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127(4):679–695

    CAS  PubMed  Google Scholar 

  4. Seyfried TN, Huysentruyt LC (2013) On the origin of cancer metastasis. Crit Rev Oncog 18(1–2):43–73

    PubMed  PubMed Central  Google Scholar 

  5. Cummings MC, Simpson PT, Reid LE, Jayanthan J, Skerman J, Song S et al (2014) Metastatic progression of breast cancer: insights from 50 years of autopsies. J Pathol 232(1):23–31

    CAS  PubMed  Google Scholar 

  6. Chen T, You Y, Jiang H, Wang ZZ (2017) Epithelial-mesenchymal transition (EMT): a biological process in the development, stem cell differentiation, and tumorigenesis. J Cell Physiol 232(12):3261–3272

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139(5):871–890

    CAS  PubMed  Google Scholar 

  8. Shaw TJ, Martin P (2009) Wound repair at a glance. J Cell Sci 122(Pt 18):3209–3213

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bonnomet A, Syne L, Brysse A, Feyereisen E, Thompson EW, Noel A et al (2012) A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene 31(33):3741–3753

    CAS  PubMed  Google Scholar 

  10. Sarrio D, Rodriguez-Pinilla SM, Hardisson D, Cano A, Moreno-Bueno G, Palacios J (2008) Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res 68(4):989–997

    CAS  PubMed  Google Scholar 

  11. Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT et al (2013) Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 339(6119):580–584

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Blanco MJ, Moreno-Bueno G, Sarrio D, Locascio A, Cano A, Palacios J et al (2002) Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21(20):3241–3246

    CAS  PubMed  Google Scholar 

  13. Come C, Magnino F, Bibeau F, De Santa BP, Becker KF, Theillet C et al (2006) Snail and slug play distinct roles during breast carcinoma progression. Clin Cancer Res 12(18):5395–5402

    CAS  PubMed  Google Scholar 

  14. Martin TA, Goyal A, Watkins G, Jiang WG (2005) Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann Surg Oncol 12(6):488–496

    PubMed  Google Scholar 

  15. Wallerand H, Robert G, Pasticier G, Ravaud A, Ballanger P, Reiter RE et al (2010) The epithelial-mesenchymal transition-inducing factor TWIST is an attractive target in advanced and/or metastatic bladder and prostate cancers. Urol Oncol 28(5):473–479

    CAS  PubMed  Google Scholar 

  16. da Silva SD, Alaoui-Jamali MA, Soares FA, Carraro DM, Brentani HP, Hier M et al (2014) TWIST1 is a molecular marker for a poor prognosis in oral cancer and represents a potential therapeutic target. Cancer 120(3):352–362

    PubMed  Google Scholar 

  17. Azimi I, Monteith GR (2016) Plasma membrane ion channels and epithelial to mesenchymal transition in cancer cells. Endocr Relat Cancer 23(11):R517–R525

    CAS  PubMed  Google Scholar 

  18. Davis FM, Azimi I, Faville RA, Peters AA, Jalink K, Putney JW Jr et al (2014) Induction of epithelial-mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Oncogene 33(18):2307–2316

    CAS  PubMed  Google Scholar 

  19. Liu J, Chen Y, Shuai S, Ding D, Li R, Luo R (2014) TRPM8 promotes aggressiveness of breast cancer cells by regulating EMT via activating AKT/GSK-3beta pathway. Tumour Biol 35(9):8969–8977

    CAS  PubMed  Google Scholar 

  20. Hu J, Qin K, Zhang Y, Gong J, Li N, Lv D et al (2011) Downregulation of transcription factor Oct4 induces an epithelial-to-mesenchymal transition via enhancement of Ca2+ influx in breast cancer cells. Biochem Biophys Res Commun 411(4):786–791

    CAS  PubMed  Google Scholar 

  21. Yu Y, Walia V, Elble RC (2013) Loss of CLCA4 promotes epithelial-to-mesenchymal transition in breast cancer cells. PLoS ONE 8(12):e83943

    PubMed  PubMed Central  Google Scholar 

  22. Walia V, Yu Y, Cao D, Sun M, McLean JR, Hollier BG et al (2012) Loss of breast epithelial marker hCLCA2 promotes epithelial-to-mesenchymal transition and indicates higher risk of metastasis. Oncogene 31(17):2237–2246

    CAS  PubMed  Google Scholar 

  23. Zhang JT, Jiang XH, Xie C, Cheng H, Da Dong J, Wang Y et al (2013) Downregulation of CFTR promotes epithelial-to-mesenchymal transition and is associated with poor prognosis of breast cancer. Biochim Biophys Acta 1833(12):2961–2969

    CAS  PubMed  Google Scholar 

  24. Eren OO, Ozturk MA, Sonmez OU, Oyan B (2015) Voltage-gated sodium channel blockers can augment the efficacy of chemotherapeutics by their inhibitory effect on epithelial-mesenchymal transition. Med Hypotheses 84(1):11–13

    CAS  PubMed  Google Scholar 

  25. Noreng S, Bharadwaj A, Posert R, Yoshioka C, Baconguis I (2018) Structure of the human epithelial sodium channel by cryo-electron microscopy. Elife. https://doi.org/10.7554/eLife.39340

    Article  PubMed  PubMed Central  Google Scholar 

  26. Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M et al (1994) Liddle’s syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel. Cell 79(3):407–414

    CAS  PubMed  Google Scholar 

  27. Strautnieks SS, Thompson RJ, Gardiner RM, Chung E (1996) A novel splice-site mutation in the gamma subunit of the epithelial sodium channel gene in three pseudohypoaldosteronism type 1 families. Nat Genet 13(2):248–250

    CAS  PubMed  Google Scholar 

  28. Rossier BC, Pradervand S, Schild L, Hummler E (2002) Epithelial sodium channel and the control of sodium balance: interaction between genetic and environmental factors. Annu Rev Physiol 64:877–897

    CAS  PubMed  Google Scholar 

  29. Drummond HA, Grifoni SC, Jernigan NL (2008) A new trick for an old dogma: ENaC proteins as mechanotransducers in vascular smooth muscle. Physiology (Bethesda) 23:23–31

    CAS  Google Scholar 

  30. Chandrashekar J, Kuhn C, Oka Y, Yarmolinsky DA, Hummler E, Ryba NJ et al (2010) The cells and peripheral representation of sodium taste in mice. Nature 464(7286):297–301

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Althaus M, Bogdan R, Clauss WG, Fronius M (2007) Mechano-sensitivity of epithelial sodium channels (ENaCs): laminar shear stress increases ion channel open probability. FASEB J 21(10):2389–2399

    CAS  PubMed  Google Scholar 

  32. Jeggle P, Callies C, Tarjus A, Fassot C, Fels J, Oberleithner H et al (2013) Epithelial sodium channel stiffens the vascular endothelium in vitro and in Liddle mice. Hypertension 61(5):1053–1059

    CAS  PubMed  Google Scholar 

  33. Yang HY, Charles RP, Hummler E, Baines DL, Isseroff RR (2013) The epithelial sodium channel mediates the directionality of galvanotaxis in human keratinocytes. J Cell Sci 126(Pt 9):1942–1951

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Grifoni SC, Gannon KP, Stec DE, Drummond HA (2006) ENaC proteins contribute to VSMC migration. Am J Physiol Heart Circ Physiol 291(6):H3076–H3086

    CAS  PubMed  Google Scholar 

  35. Xu W, Mezencev R, Kim B, Wang L, McDonald J, Sulchek T (2012) Cell stiffness is a biomarker of the metastatic potential of ovarian cancer cells. PLoS ONE 7(10):e46609

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Plodinec M, Loparic M, Monnier CA, Obermann EC, Zanetti-Dallenbach R, Oertle P et al (2012) The nanomechanical signature of breast cancer. Nat Nanotechnol 7(11):757–765

    CAS  PubMed  Google Scholar 

  37. Swaminathan V, Mythreye K, O’Brien ET, Berchuck A, Blobe GC, Superfine R (2011) Mechanical stiffness grades metastatic potential in patient tumor cells and in cancer cell lines. Cancer Res 71(15):5075–5080

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sparks RL, Pool TB, Smith NK, Cameron IL (1983) Effects of amiloride on tumor growth and intracellular element content of tumor cells in vivo. Cancer Res 43(1):73–77

    CAS  PubMed  Google Scholar 

  39. He M, Liu S, Gallolu Kankanamalage S, Borromeo MD, Girard L, Gazdar AF et al (2018) The epithelial sodium channel (alphaENaC) is a downstream therapeutic target of ASCL1 in pulmonary neuroendocrine tumors. Transl Oncol 11(2):292–299

    PubMed  PubMed Central  Google Scholar 

  40. Rooj AK, McNicholas CM, Bartoszewski R, Bebok Z, Benos DJ, Fuller CM (2012) Glioma-specific cation conductance regulates migration and cell cycle progression. J Biol Chem 287(6):4053–4065

    CAS  PubMed  Google Scholar 

  41. Kapoor N, Bartoszewski R, Qadri YJ, Bebok Z, Bubien JK, Fuller CM et al (2009) Knockdown of ASIC1 and epithelial sodium channel subunits inhibits glioblastoma whole cell current and cell migration. J Biol Chem 284(36):24526–24541

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Del Monaco SM, Marino GI, Assef YA, Damiano AE, Kotsias BA (2009) Cell migration in BeWo cells and the role of epithelial sodium channels. J Membr Biol 232(1–3):1–13

    CAS  PubMed  Google Scholar 

  43. Marino GI, Assef YA, Kotsias BA (2013) The migratory capacity of human trophoblastic BeWo cells: effects of aldosterone and the epithelial sodium channel. J Membr Biol 246(3):243–255

    CAS  PubMed  Google Scholar 

  44. Boyd C, Naray-Fejes-Toth A (2007) Steroid-mediated regulation of the epithelial sodium channel subunits in mammary epithelial cells. Endocrinology 148(8):3958–3967

    CAS  PubMed  Google Scholar 

  45. Wang Q, Schultz BD (2014) Cholera toxin enhances Na(+) absorption across MCF10A human mammary epithelia. Am J Physiol Cell Physiol 306(5):C471–C484

    CAS  PubMed  Google Scholar 

  46. Amara S, Ivy MT, Myles EL, Tiriveedhi V (2016) Sodium channel gammaENaC mediates IL-17 synergized high salt induced inflammatory stress in breast cancer cells. Cell Immunol 302:1–10

    CAS  PubMed  Google Scholar 

  47. Rhodes LV, Antoon JW, Muir SE, Elliott S, Beckman BS, Burow ME (2010) Effects of human mesenchymal stem cells on ER-positive human breast carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk. Mol Cancer 9:295

    PubMed  PubMed Central  Google Scholar 

  48. Espinoza-Sanchez NA, Vadillo E, Balandran JC, Monroy-Garcia A, Pelayo R, Fuentes-Panana EM (2017) Evidence of lateral transmission of aggressive features between different types of breast cancer cells. Int J Oncol 51(5):1482–1496

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y et al (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767

    CAS  PubMed  PubMed Central  Google Scholar 

  50. McDonald FJ, Price MP, Snyder PM, Welsh MJ (1995) Cloning and expression of the beta- and gamma-subunits of the human epithelial sodium channel. Am J Physiol 268(5 Pt 1):C1157–C1163

    CAS  PubMed  Google Scholar 

  51. Saal LH, Vallon-Christersson J, Hakkinen J, Hegardt C, Grabau D, Winter C et al (2015) The Sweden Cancerome Analysis Network - Breast (SCAN-B) Initiative: a large-scale multicenter infrastructure towards implementation of breast cancer genomic analyses in the clinical routine. Genome Med 7(1):20

    PubMed  PubMed Central  Google Scholar 

  52. Omnibus GE (2020) http://www.ncbi.nlm.nih.gov/geo/

  53. Nagalla S, Chou JW, Willingham MC, Ruiz J, Vaughn JP, Dubey P et al (2013) Interactions between immunity, proliferation and molecular subtype in breast cancer prognosis. Genome Biol 14(4):R34

    PubMed  PubMed Central  Google Scholar 

  54. Mak MP, Tong P, Diao L, Cardnell RJ, Gibbons DL, William WN et al (2016) A patient-derived, pan-cancer EMT signature identifies global molecular alterations and immune target enrichment following epithelial-to-mesenchymal transition. Clin Cancer Res 22(3):609–620

    CAS  PubMed  Google Scholar 

  55. Banerjee S, Reis-Filho JS, Ashley S, Steele D, Ashworth A, Lakhani SR et al (2006) Basal-like breast carcinomas: clinical outcome and response to chemotherapy. J Clin Pathol 59(7):729–735

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Wang TC, Cheng CY, Yang WH, Chen WC, Chang PJ (2015) Characterization of highly proliferative secondary tumor clusters along host blood vessels in malignant glioma. Mol Med Rep 12(5):6435–6444

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Aguilar E, Marin de Mas I, Zodda E, Marin S, Morrish F, Selivanov V et al (2016) Metabolic reprogramming and dependencies associated with epithelial cancer stem cells independent of the epithelial-mesenchymal transition program. Stem Cells 34(5):1163–1176

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Sheng S, Li J, McNulty KA, Kieber-Emmons T, Kleyman TR (2001) Epithelial sodium channel pore region structure and role in gating. J Biol Chem 276(2):1326–1334

    CAS  PubMed  Google Scholar 

  59. Priestley P, Baber J, Lolkema MP, Steeghs N, de Bruijn E, Shale C et al (2019) Pan-cancer whole-genome analyses of metastatic solid tumours. Nature 575(7781):210–216

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q et al (2010) 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(3):725–731

    PubMed  Google Scholar 

  61. Mittal V (2018) Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol 13:395–412

    CAS  PubMed  Google Scholar 

  62. Armstrong AJ, Marengo MS, Oltean S, Kemeny G, Bitting RL, Turnbull JD et al (2011) Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Mol Cancer Res 9(8):997–1007

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Kallergi G, Papadaki MA, Politaki E, Mavroudis D, Georgoulias V, Agelaki S (2011) Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res 13(3):R59

    PubMed  PubMed Central  Google Scholar 

  64. Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S et al (2012) Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell 22(6):709–724

    CAS  PubMed  Google Scholar 

  65. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J (2012) Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 22(6):725–736

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Salt MB, Bandyopadhyay S, McCormick F (2014) Epithelial-to-mesenchymal transition rewires the molecular path to PI3K-dependent proliferation. Cancer Discov 4(2):186–199

    CAS  PubMed  Google Scholar 

  67. Chavez KJ, Garimella SV, Lipkowitz S (2010) Triple negative breast cancer cell lines: one tool in the search for better treatment of triple negative breast cancer. Breast Dis 32(1–2):35–48

    PubMed  PubMed Central  Google Scholar 

  68. Vogt PK, Kang S, Elsliger MA, Gymnopoulos M (2007) Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci 32(7):342–349

    CAS  PubMed  Google Scholar 

  69. Khotskaya YB, Goverdhan A, Shen J, Ponz-Sarvise M, Chang SS, Hsu MC et al (2014) S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer. Am J Transl Res 6(4):361–376

    PubMed  PubMed Central  Google Scholar 

  70. Kao CL, Hsu HS, Chen HW, Cheng TH (2009) Rapamycin increases the p53/MDM2 protein ratio and p53-dependent apoptosis by translational inhibition of mdm2 in cancer cells. Cancer Lett 286(2):250–259

    CAS  PubMed  Google Scholar 

  71. Kuo YH, Chiang EI, Chao CY, Rodriguez RL, Chou PY, Tsai SY et al (2017) Dual inhibition of key proliferation signaling pathways in triple-negative breast cancer cells by a novel derivative of Taiwanin A. Mol Cancer Ther 16(3):480–493

    CAS  PubMed  Google Scholar 

  72. Knoepp F, Ashley Z, Barth D, Baldin JP, Jennings M, Kazantseva M et al (2020) Shear force sensing of epithelial Na(+) channel (ENaC) relies on N-glycosylated asparagines in the palm and knuckle domains of alphaENaC. Proc Natl Acad Sci USA 117(1):717–726

    CAS  PubMed  Google Scholar 

  73. Knoepp F, Ashley Z, Barth D, Kazantseva M, Szczesniak PP, Clauss WG, Althaus M, de la Rosa DA, Fronius M (2017) Mechanical activation of epithelial Na+ channel relies on interdependent activity of the extracelullar matrix and extracellular N-glycans of αENaC. BioRxiv

  74. Giancotti FG, Ruoslahti E (1999) Integrin signaling. Science 285(5430):1028–1032

    CAS  PubMed  Google Scholar 

  75. Zhao J, Pestell R, Guan JL (2001) Transcriptional activation of cyclin D1 promoter by FAK contributes to cell cycle progression. Mol Biol Cell 12(12):4066–4077

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Schrader J, Gordon-Walker TT, Aucott RL, van Deemter M, Quaas A, Walsh S et al (2011) Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53(4):1192–1205

    CAS  PubMed  Google Scholar 

  77. Tzanakakis G, Kavasi RM, Voudouri K, Berdiaki A, Spyridaki I, Tsatsakis A et al (2018) Role of the extracellular matrix in cancer-associated epithelial to mesenchymal transition phenomenon. Dev Dyn 247(3):368–381

    PubMed  Google Scholar 

  78. Hanukoglu I, Hanukoglu A (2016) Epithelial sodium channel (ENaC) family: phylogeny, structure-function, tissue distribution, and associated inherited diseases. Gene 579(2):95–132

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Tatsuta M, Iishi H, Baba M, Yano H, Iseki K, Uehara H et al (1996) Inhibition by amiloride of experimental carcinogenesis induced by azaserine in rat pancreas. Cancer Lett 106(1):23–28

    CAS  PubMed  Google Scholar 

  80. Tatsuta M, Iishi H, Baba M, Yano H, Sakai N, Uehara H et al (1997) Chemoprevention by amiloride against experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Cancer Lett 119(1):109–113

    CAS  PubMed  Google Scholar 

  81. Jankun J, Keck RW, Skrzypczak-Jankun E, Swiercz R (1997) Inhibitors of urokinase reduce size of prostate cancer xenografts in severe combined immunodeficient mice. Cancer Res 57(4):559–563

    CAS  PubMed  Google Scholar 

  82. Ray P, Bhatti R, Gadarowski J, Bell N, Nasruddin S (1998) Inhibitory effect of amiloride on the urokinase plasminogen activators in prostatic cancer. Tumour Biol 19(1):60–64

    CAS  PubMed  Google Scholar 

  83. Zheng YT, Yang HY, Li T, Zhao B, Shao TF, Xiang XQ et al (2015) Amiloride sensitizes human pancreatic cancer cells to erlotinib in vitro through inhibition of the PI3K/AKT signaling pathway. Acta Pharmacol Sin 36(5):614–626

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Rojas EA, Corchete LA, San-Segundo L, Martinez-Blanch JF, Codoner FM, Paino T et al (2017) Amiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma. Clin Cancer Res 23(21):6602–6615

    CAS  PubMed  Google Scholar 

  85. Kellen JA, Mirakian A, Kolin A (1988) Antimetastatic effect of amiloride in an animal tumour model. Anticancer Res 8(6):1373–1376

    CAS  PubMed  Google Scholar 

  86. Evans DM, Sloan-Stakleff KD (1998) Maximum effect of urokinase plasminogen activator inhibitors in the control of invasion and metastasis of rat mammary cancer. Invasion Metastasis 18(5–6):252–260

    CAS  PubMed  Google Scholar 

  87. Evans DM, Sloan-Stakleff K, Arvan M, Guyton DP (1998) Time and dose dependency of the suppression of pulmonary metastases of rat mammary cancer by amiloride. Clin Exp Metastasis 16(4):353–357

    CAS  PubMed  Google Scholar 

  88. Leon LJ, Pasupuleti N, Gorin F, Carraway KL 3rd (2013) A cell-permeant amiloride derivative induces caspase-independent, AIF-mediated programmed necrotic death of breast cancer cells. PLoS ONE 8(4):e63038

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Bigiani A (2020) Does ENaC work as sodium taste receptor in humans? Nutrients 12(4):1195

    CAS  PubMed Central  Google Scholar 

  90. Slepkov ER, Rainey JK, Sykes BD, Fliegel L (2007) Structural and functional analysis of the Na+/H+ exchanger. Biochem J 401(3):623–633

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Stepanova V, Dergilev KV, Holman KR, Parfyonova YV, Tsokolaeva ZI, Teter M et al (2017) Urokinase-type plasminogen activator (uPA) is critical for progression of tuberous sclerosis complex 2 (TSC2)-deficient tumors. J Biol Chem 292(50):20528–20543

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank Dr Noelyn Hung, Dr Michael Landmann, and Dr Simone Petrich for the collection of breast tissue samples used in the immunohistochemistry experiments and Associate Professor Mik Black for statistical advice.

Funding

The authors gratefully acknowledge funding from the Department of Physiology, University of Otago; Maurice and Phyllis Paykel Trust; Lottery Health New Zealand (R-LHR-2019-101706); School of Biomedical Sciences Dean’s Grant; and University of Otago Research Grant (ORG 0118-0319).

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Authors and Affiliations

  1. Department of Physiology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand

    Adam W. Ware & Fiona J. McDonald

  2. Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

    Joshua J. Harris, Tania L. Slatter & Heather E. Cunliffe

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  1. Adam W. Ware
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Contributions

FM, HC, AW, and JH conceived and designed the study. AW carried out the experiments. JH performed bioinformatic analysis. TS provided breast cancer tissue sections. AW, JH, and HC analyzed the data. AW, JH, and FM drafted the manuscript. All authors read and approved the manuscript.

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Correspondence to Fiona J. McDonald.

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The authors declare that there are no competing interests.

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Ethical approval was obtained from the Lower South Regional Ethics Committee, Ministry of Health, New Zealand, and all participating women gave written and informed consent for inclusion in the study.

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Ware, A.W., Harris, J.J., Slatter, T.L. et al. The epithelial sodium channel has a role in breast cancer cell proliferation. Breast Cancer Res Treat 187, 31–43 (2021). https://doi.org/10.1007/s10549-021-06133-7

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