Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

Protein kinase CK2 in mammary gland tumorigenesis

Abstract

Protein kinase CK2 is a ubiquitous and evolutionarily conserved serine/threonine kinase that is upregulated in many human cancers and can serve as an oncogene in lymphocytes. Recently, we have demonstrated that CK2 potentiates Wnt/β-catenin signaling in mammary epithelial cells. To determine whether CK2 overexpression contributes to mammary tumorigenesis, we have performed comparative studies of human and rat breast cancer specimens and we have engineered transgenic mice with dysregulated expression of CK2α in the mammary gland. We find that CK2 is highly expressed in human breast tumor specimens and in carcinogen-induced rat mammary tumors. Overexpression of CK2α in the mammary gland of transgenic mice, under control of the MMTV-LTR, causes hyperplasia and dysplasia of the female mammary gland. Thirty per cent of the female MMTV-CK2α transgenic mice develop mammary adenocarcinomas at a median of 23 months of age, often associated with Wnt pathway activation, as evidenced by upregulation of β-catenin protein. NF-κB activation and upregulation of c-Myc also occur frequently. Thus, in mice, rats, and humans, dysregulated expression of CK2 is associated with and is capable of contributing to mammary tumorigenesis. Targeted inhibition of CK2 could be useful in the treatment of breast cancer.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  • Adam L, Vadlamudi R, Kondapaka SB, Chernoff J, Mendelsohn J, Kumar R . 1998 J. Biol. Chem. 273: 28238–28246

  • Ahmed K . 1994 Cell. Mol. Biol. Res. 40: 1–11

  • Allende JE, Allende CC . 1995 FASEB J. 9: 313–323

  • Arsura M, FitzGerald MJ, Fausto N, Sonenshein GE . 1997 Cell Growth Differ. 8: 1049–1059

  • Barker N, Huls G, Korinek V, Clevers H . 1999 Am. J. Pathol. 154: 29–35

  • Birchmeier C, Birchmeier W, Brand-Saberi B . 1996 Acta. Anat. 156: 217–226

  • Bird TA, Schooley K, Dower SK, Hagen H, Virca GD . 1997 J. Biol. Chem. 272: 32606–32612

  • Bren GD, Pennington KN, Paya CV . 2000 J. Mol. Biol. 297: 1245–1258

  • Bui TD, Rankin J, Smith K, Huguet EL, Ruben S, Strachan T, Harris AL, Lindsay S . 1997 Oncogene 14: 1249–1253

  • Cardiff RD . 1996 J. Mammary Gland Biol. Neoplasia 1: 61–73

  • Cardiff RD, Wellings SR . 1999 J. Mammary Gland Biol. Neoplasia 4: 105–122

  • Chirgwin JM, Przybyla AE, MacDonald RJ, Rutter WJ . 1979 Biochemistry 18: 5294–5299

  • Dale TC, Weber-Hall SJ, Smith K, Huguet EL, Jayatilake H, Gusterson BA, Shuttleworth G, O'Hare M, Harris AL . 1996 Cancer Res. 56: 4320–4323

  • Daya-Makin M, Sanghera JS, Mogentale TL, Lipp M, Parchomchuk J, Hogg JC, Pelech SL . 1994 Cancer Res. 54: 2262–2268

  • Duyao MP, Buckler AJ, Sonenshein GE . 1990 Proc. Natl. Acad. Sci. USA 87: 4727–4731

  • Faust RA, Gapany M, Tristani P, Davis A, Adams GL, Ahmed K . 1996 Cancer Lett. 101: 31–35

  • Foo SY, Nolan GP . 1999 Trends Genet. 15: 229–235

  • Ford HL, Landesman-Bollag E, Dacwag CS, Stukenberg PT, Pardee AB, Seldin DC . 2000 J. Biol. Chem. 275: 22245–22254

  • Gapany M, Faust RA, Tawfic S, Davis A, Adams GL, Ahmed K . 1995 Mol. Med. 1: 659–666

  • Glover III CV . 1998 Prog. Nucleic. Acid. Res. Mol. Biol. 59: 95–133

  • Guerra B, Issinger OG . 1999 Electrophoresis 20: 391–408

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW . 1998 Science 281: 1509–1512

  • Heilker R, Freuler F, Pulfer R, Di Padova F, Eder J . 1999 Eur. J. Biochem. 259: 253–261

  • Heller-Harrison RA, Meisner H, Czech MP . 1989 Biochemistry 28: 9053–9058

  • Howard DK, Schlom J, Fischer PB . 1983 In Vitro 19: 58–66

  • Huggins C, Grand LC, Brillantes FP . 1961 Nature 189: 204–207

  • Huguet EL, McMahon JA, McMahon AP, Bicknell R, Harris AL . 1994 Cancer Res. 54: 2615–2621

  • Israel A . 2000 Trends Cell Biol. 10: 129–133

  • Issinger OG . 1993 Pharmacol. Ther. 59: 1–30

  • Janosch P, Schellerer M, Seitz T, Reim P, Eulitz M, Brielmeier M, Kolch W, Sedivy JM, Mischak H . 1996 J. Biol. Chem. 271: 13868–13874

  • Johnson GG, Kronert WA, Bernstein SI, Chapman VM, Smith KD . 1988 J. Biol. Chem. 263: 9079–9082

  • Kelliher MA, Seldin DC, Leder P . 1996 EMBO J. 15: 5160–5166

  • Kessler DJ, Duyao MP, Spicer DB, Sonenshein GE . 1992 J. Exp. Med. 176: 787–792

  • Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW, Hafer LJ, Yaswen P, Stampfer M, Rogers AE, Russo J, Sonenshein GE . 2000 Carcinogenesis 21: 871–879

  • Kuenzel EA, Mulligan JA, Sommercorn J, Krebs EG . 1987 J. Biol. Chem. 262: 9136–9140

  • Kuhl M, Sheldahl LC, Park M, Miller JR, Moon RT . 2000 Trends Genet. 16: 279–283

  • Laemmli UK . 1970 Nature 227: 680–685

  • Landesman-Bollag E, Channavajhala PL, Cardiff RD, Seldin DC . 1998 Oncogene 16: 2965–2974

  • Lin R, Beauparlant P, Makris C, Meloche S, Hiscott J . 1996 Mol. Cell Biol. 16: 1401–1409

  • Liu ZP, Galindo RL, Wasserman SA . 1997 Genes Dev. 11: 3413–3422

  • Mahler JF, Stokes W, Mann PC, Takaoka M, Maronpot RR . 1996 Toxicol. Pathol. 24: 710–716

  • McElhinny JA, Trushin SA, Bren GD, Chester N, Paya CV . 1996 Mol. Cell. Biol. 16: 899–906

  • Mestres P, Boldyreff B, Ebensperger C, Hameister H, Issinger OG . 1994 Acta. Anat. 149: 13–20

  • Mitev V, Miteva L, Botev I, Houdebine LM . 1994 J. Dermatol. Sci. 8: 45–49

  • Morin PJ, Sparks AB, Korinek V, Barker N, Clevers H, Vogelstein B, Kinzler KW . 1997 Science 275: 1787–1790

  • Morris JJ, Seifter E . 1992 Med. Hypotheses 38: 177–184

  • Munstermann U, Fritz G, Seitz G, Lu YP, Schneider HR, Issinger OG . 1990 Eur. J. Biochem. 189: 251–257

  • Nakshatri H, Bhat-Nakshatri P, Martin DA, Goulet Jr RJ, Sledge Jr GW . 1997 Mol. Cell. Biol. 17: 3629–3639

  • Nebert DW, Jaiswal AK, Meyer UA, Gonzalez FJ . 1987 Biochem. Soc. Trans. 15: 586–589

  • Nusse R, Varmus HE . 1982 Cell 31: 99–109

  • Ohi Y, Yoshida H . 1992 Virchows Arch. B Cell. Pathol. Inc. Mol. Pathol. 62: 365–370

  • ole-MoiYoi OK, Brown WC, Iams KP, Nayar A, Tsukamoto T, Macklin MD . 1993 EMBO J. 12: 1621–1631

  • Orlandini M, Semplici F, Ferruzzi R, Meggio F, Pinna LA, Oliviero S . 1998 J. Biol. Chem. 273: 21291–21297

  • Pancetti F, Bosser R, Itarte E, Bachs O . 1996 Biochem. Biophys. Res. Commun. 218: 35–39

  • Pando MP, Verma IM . 2000 J. Biol. Chem. 275: 21278–21286

  • Pena JM, Itarte E, Domingo A, Cusso R . 1983 Cancer Res. 43: 1172–1175

  • Pepperkok R, Lorenz P, Ansorge W, Pyerin W . 1994 J. Biol. Chem. 269: 6986–6991

  • Perez M, Grande J, Itarte E . 1988 FEBS Lett. 238: 273–276

  • Perfetti V, Manenti G, Dragani TA . 1991 Leukemia 5: 1110–1112

  • Pinna LA, Meggio F . 1997 Prog. Cell Cycle Res. 3: 77–97

  • Polakis P . 1999 Curr. Opin. Genet. Dev. 9: 15–21

  • Randerath E, Agrawal HP, Weaver JA, Bordelon CB, Randerath K . 1985 Carcinogenesis 6: 1117–1126

  • Rogers AE, Wetsel WC . 1981 Cancer. Res. 41: 3735–3737

  • Roig J, Krehan A, Colomer D, Pyerin W, Itarte E, Plana M . 1999 Mol. Cell. Biochem. 191: 229–234

  • Romieu-Mourez R, Landesman-Bollag E, Seldin DC, Traish AM, Mercurio F, Sonenshein GE . 2001 Cancer Res. (in press)

  • Roose J, Clevers H . 1999 Biochim. Biophys. Acta 1424: M23–M37

  • Safe S . 1984 Crit. Rev. Toxicol. 13: 319–395

  • Schlosshauer PW, Brown SA, Eisinger K, Yan Q, Guglielminetti ER, Parsons R, Ellenson LH, Kitajewski J . 2000 Carcinogenesis 21: 1453–1456

  • Schwarz EM, Van AD, Verma IM . 1996 Mol. Cell. Biol. 16: 3554–3559

  • Seldin DC, Leder P . 1995 Science 267: 894–897

  • Sinn E, Muller W, Pattengale P, Tepler I, Wallace R, Leder P . 1987 Cell 49: 465–475

  • Song DH, Sussman DJ, Seldin DC . 2000 J. Biol. Chem. 275: 23790–23797

  • Sovak MA, Bellas RE, Kim DW, Zanieski GJ, Rogers AE, Traish AM, Sonenshein GE . 1997 J. Clin. Invest. 100: 2952–2960

  • Stewart TA, Pattengale PK, Leder P . 1984 Cell 38: 627–637

  • Toczyski DP, Galgoczy DJ, Hartwell LH . 1997 Cell 90: 1097–1106

  • Tran K, Merika M, Thanos D . 1997 Mol. Cell. Biol. 17: 5386–5399

  • Tsukamoto AS, Grosschedl R, Guzman RC, Parslow T, Varmus HE . 1988 Cell 55: 619–625

  • Webster MA, Hutchinson JN, Rauh MJ, Muthuswamy SK, Anton M, Tortorice CG, Cardiff RD, Graham FL, Hassell JA, Muller WJ . 1998 Mol. Cell. Biol. 18: 2344–2359

  • Willert K, Brink M, Wodarz A, Varmus H, Nusse R . 1997 EMBO J. 16: 3089–3096

  • Xu, X, Toselli PA, Russell LD, Seldin Dc . 1999 Nat. Genet. 23: 118–121

Download references

Acknowledgements

We thank Drs Adrianne Rogers, Carol Rosenberg, and Abdul Traish in the Departments of Pathology and Medicine at Boston University School of Medicine for providing breast tumor and tissue specimens from rats and from human patients; Anne Harrington and Philip Leder in the Genetics Department at Harvard Medical School for transgenic injections; Judy E Walls in the Transgenic Mouse Core Histopathology Laboratory at UC. Davis School of Medicine for outstanding technical work on the histology and immunohistochemistry; and members of the Seldin and Sonenshein laboratories for helpful comments and review of the manuscript. This work was supported by the Massachusetts Department of Public Health Breast Cancer Training Program (E Landesman-Bollag, DH Song and DC Seldin); by the Association pour la Recherche sur le Cancer (R Romieu-Mourez) and the Fondation Bettencourt-Schueller (R Romieu-Mourez); the Department of Defense DAMD 17-98-1 (GE Sonenschein, DC Seldin); NIH RO1 CA 82742 (GE Sonenshein, DC Seldin); and by the University of California Breast Cancer Research Program grant #JB-0014 (RD Cardiff).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Landesman-Bollag, E., Romieu-Mourez, R., Song, D. et al. Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20, 3247–3257 (2001). https://doi.org/10.1038/sj.onc.1204411

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1204411

Keywords

This article is cited by

Search

Quick links