Skip to main content
SpringerLink
Log in

NF-κB in Mammary Gland Development and Breast Cancer

  • Published:
Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Nuclear factor of κB (NF-κB) is a group of sequence-specific transcription factors that is best known as a key regulator of the inflammatory and innate immune responses. Recent studies of genetically engineered mice have clearly indicated that NF-κB is also required for proper organogenesis of several epithelial tissues, including the mammary gland. Mice have shown severe lactation deficiency when NF-κB activation is specifically blocked in the mammary gland. In addition, there are strong suggestions that NF-κB may play an important role in the etiology of breast cancer. Elevated NF-κB DNA-binding activity is detected in both mammary carcinoma cell lines and primary human breast cancer tissues.

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

Similar content being viewed by others

REFERENCES

  1. S. Ghosh and M. Karin (2002). Missing pieces in the NF-κB puzzle. Cell 109(Suppl):S81-S96.

    PubMed  Google Scholar 

  2. M. Karin and A. Lin (2002). NF-κB at the crossroads of life and death. Nat. Immunol. 3:221–227.

    PubMed  Google Scholar 

  3. D. M. Rothwarf and M. Karin (1999). The NF-κB activation pathway: A paradigm in information transfer from membrane to nucleus. Sci. STKE 1999:RE1.

    PubMed  Google Scholar 

  4. M. J. May and S. Ghosh (1997). Rel/NF-κB and IκB proteins: An overview. Semin. Cancer Biol. 8:63–73.

    PubMed  Google Scholar 

  5. I. Verma, J. Stevenson, E. Schwarz, D. Van Antwerp, and S. Miyamoto (1995). Rel/NF-κB/IκB family: Intimate tales of association and dissociation. Genes Dev. 9:2723–2735.

    PubMed  Google Scholar 

  6. M. Karin and Y. Ben-Neriah (2000). Phosphorylation meets ubiquitination: The control of NF-[κ]B activity. Annu. Rev. Immunol. 18:621–663.

    PubMed  Google Scholar 

  7. E. Dejardin, N. M. Droin, M. Delhase, E. Haas, Y. Cao, C. Makris, et al. (2002). The lymphotoxin-beta receptor induces different patterns of gene expression via two NF-κB pathways. Immunity 17: 525–535.

    PubMed  Google Scholar 

  8. H. Pahl (1999). Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18: 6853–6866.

    PubMed  Google Scholar 

  9. M. Karin, Y. Cao, F. R. Greten, and Z. W. Li (2002). NF-κB in cancer: From innocent bystander to major culprit. Nature Rev. Cancer 2:301–310.

    Google Scholar 

  10. B. Rayet and C. Gelinas (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938–6947.

    PubMed  Google Scholar 

  11. T. Gilmore, M. Koedood, K. Piffat, and D. White (1996). Rel/NF-κB/IκB proteins and cancer. Oncogene 13: 1367–1378.

    PubMed  Google Scholar 

  12. L. Hennighausen and G. W. Robinson (2001). Signaling pathways in mammary gland development. Dev. Cell 1:467–475.

    PubMed  Google Scholar 

  13. L. Hennighausen and G. W. Robinson (1998). Think globally, act locally: The making of a mouse mammary gland. Genes Dev. 12: 449–455.

    PubMed  Google Scholar 

  14. D. M. Brantley, F. E. Yull, R. S. Muraoka, D. J. Hicks, C. M. Cook, and L. D. Kerr (2000). Dynamic expression and activity of NF-κB during post-natal mammary gland morphogenesis. Mech. Dev. 97:149–155.

    PubMed  Google Scholar 

  15. R. W. Clarkson, J. L. Heeley, R. Chapman, F. Aillet, R. T. Hay, A. Wyllie, et al. (2000). NF-κB inhibits apoptosis in murine mammary epithelia. J. Biol. Chem. 275: 12737–12742.

    PubMed  Google Scholar 

  16. S. Geymayer and W. Doppler (2000). Activation of NF-κB p50/p65 is regulated in the developing mammary gland and inhibits STAT5-mediated beta-casein gene expression. FASEB J. 14:1159–1170.

    PubMed  Google Scholar 

  17. D. M. Brantley, C. L. Chen, R. S. Muraoka, P. B. Bushdid, J. L. Bradberry, F. Kittrell, et al. (2001). Nuclear factor-κB (NF-κB) regulates proliferation and branching in mouse mammary epithelium. Mol. Biol. Cell 12:1445–1455.

    PubMed  Google Scholar 

  18. Y. Cao, G. Bonizzi, T. N. Seagroves, F. R. Greten, R. Johnson, E. V. Schmidt, et al. (2001). IKKalpha provides an essential link between RANK signaling and cyclin D1 expression during mammary gland development. Cell 107: 763–775.

    PubMed  Google Scholar 

  19. J. M. Shillingford, K. Miyoshi, G. W. Robinson, B. Bierie, Y. Cao, M. Karin, et al. (2003). Proteotyping of mammary tissue from transgenic and gene knockout mice with immunohistochemical markers. A tool to define developmental lesions. J. Histochem. Cytochem. 51: 555–565.

    PubMed  Google Scholar 

  20. G. Luo and L. Yu-Lee (2000). Stat5b inhibits NF-kB-mediated signaling. Mol. Endocrinol. 14: 114–123.

    PubMed  Google Scholar 

  21. Y. Wang, T. R. Wu, S. Cai, T. Welte, and Y. E. Chin (2000). Stat1 as a component of tumor necrosis factor alpha receptor 1-TRADD signaling complex to inhibit NF-κB activation. Mol. Cell. Biol. 20: 4505–4512.

    PubMed  Google Scholar 

  22. R. W. Clarkson and C. J. Watson (1999). NF-κB and apoptosis in mammary epithelial cells. J. Mammary Gland Biol. Neoplasia 4:165–175.

    PubMed  Google Scholar 

  23. L. E. Theill, W. J. Boyle, and J. M. Penninger (2002). RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu. Rev. Immunol. 20:795–823.

    PubMed  Google Scholar 

  24. J. E. Fata, Y. Y. Kong, J. Li, T. Sasaki, J. Irie-Sasaki, R. A. Moorehead, et al. (2000). The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 103:41–50.

    PubMed  Google Scholar 

  25. L. Varela and M. Ip (1996). Tumor necrosis factor-alpha:A multifunctional regulator of mammary gland development. Endocrinology 137:4915–4924.

    PubMed  Google Scholar 

  26. P. Sicinski, J. L. Donaher, S. B. Parker, T. Li, A. Fazeli, H. Gardner, et al. (1995). Cyclin D1 provides a link between development and oncogenesis in the retina and breast. Cell 82:621–630.

    PubMed  Google Scholar 

  27. V. Fantl, G. Stamp, A. Andrews, I. Rosewell, and C. Dickson (1995). Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. Genes Dev. 9:2364–2372.

    PubMed  Google Scholar 

  28. O. N. Ozes, L. D. Mayo, J. A. Gustin, S. R. Pfeffer, L. M. Pfeffer, and D. B. Donner (1999). NF-κB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401:82–85.

    PubMed  Google Scholar 

  29. J. A. Romashkova and S. S. Makarov (1999). NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90.

    PubMed  Google Scholar 

  30. K. L. Schwertfeger, M. M. Richert, and S. M. Anderson (2001). Mammary gland involution is delayed by activated Akt in transgenic mice. Mol. Endocrinol. 15:867–881.

    PubMed  Google Scholar 

  31. J. Hutchinson, J. Jin, R. D. Cardiff, J. R. Woodgett, and W. J. Muller (2001). Activation of Akt (protein kinase B) in mammary epithelium provides a critical cell survival signal required for tumor progression. Mol. Cell. Biol. 21:2203–2212.

    PubMed  Google Scholar 

  32. S. Gerondakis, M. Grossmann, Y. Nakamura, T. Pohl, and R. Grumont (1999). Genetic approaches in mice to understand Rel/NF-kB and IkB functions: Transgenics and knockouts. Oncogene 18:6888–6895.

    PubMed  Google Scholar 

  33. A. A. Beg, W. C. Sha, R. T. Bronson, S. Ghosh, and D. Baltimore (1995). Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376:167–170.

    PubMed  Google Scholar 

  34. Z. W. Li, W. Chu, Y. Hu, M. Delhase, T. Deerinck, M. Ellisman, et al. (1999). The IKKbeta subunit of IκB kinase (IKK) is essential for nuclear factor κB activation and prevention of apoptosis. J. Exp. Med. 189:1839–1845.

    PubMed  Google Scholar 

  35. C. Makris, V. L. Godfrey, G. Krahn-Senftleben, T. Takahashi, J. L. Roberts, T. Schwarz, et al. (2000). Female mice heterozygous for IKK gamma/NEMO deficiencies develop a dermatopathy similar to the human X-linked disorder incontinentia pigmenti. Mol. Cell 5:969–979.

    PubMed  Google Scholar 

  36. P. C. Cogswell, D. C. Guttridge, W. K. Funkhouser, and A. S. BaldwinJr. (2000). Selective activation of NF-κB subunits in human breast cancer: Potential roles for NF-κB2/p52 and for Bcl-3. Oncogene 19:1123–1131.

    PubMed  Google Scholar 

  37. H. Nakshatri, P. Bhat-Nakshatri, D. A. Martin, R. J. GouletJr., and G. W. SledgeJr. (1997). Constitutive activation of NF-κB during progression of breast cancer to hormone-independent growth. Mol. Cell. Biol. 17:3629–3639.

    PubMed  Google Scholar 

  38. M. A. Sovak, R. E. Bellas, D. W. Kim, G. J. Zanieski, A. E. Rogers, A. M. Traish, et al. (1997). Aberrant nuclear factor-κB/Rel expression and the pathogenesis of breast cancer. J. Clin. Invest. 100:2952–2960.

    PubMed  Google Scholar 

  39. R. Romieu-Mourez, E. Landesman-Bollag, D. C. Seldin, A. M. Traish, F. Mercurio, and G. E. Sonenshein (2001). Roles of IKK kinases and protein kinase CK2 in activation of nuclear factor-κB in breast cancer. Cancer Res. 61:3810–3818.

    PubMed  Google Scholar 

  40. D. W. Kim, M. A. Sovak, G. Zanieski, G. Nonet, R. Romieu-Mourez, A. W. Lau, et al. (2000). Activation of NF-κB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis 21:871–879.

    PubMed  Google Scholar 

  41. D. K. Biswas, S. C. Dai, A. Cruz, B. Weiser, E. Graner, and A. B. Pardee (2001). The nuclear factor κB (NF-κB): A potential therapeutic target for estrogen receptor negative breast cancers. Proc. Natl. Acad. Sci. U.S.A. 98:10386–10391.

    PubMed  Google Scholar 

  42. M. A. Sovak, M. Arsura, G. Zanieski, K. T. Kavanagh, and G. E. Sonenshein (1999). The inhibitory effects of transforming growth factor beta1 on breast cancer cell proliferation are mediated through regulation of aberrant nuclear factor-κB/Rel expression. Cell Growth Differ. 10:537–544.

    PubMed  Google Scholar 

  43. E. Dejardin, G. Bonizzi, A. Bellahcene, V. Castronovo, M. P. Merville, and V. Bours (1995). Highly-expressed p100/p52 (NFKB2) sequesters other NF-κB-related proteins in the cytoplasm of human breast cancer cells. Oncogene 11:1835–1841.

    PubMed  Google Scholar 

  44. S. D. Westerheide, M. W. Mayo, V. Anest, J. L. Hanson, and A. S. BaldwinJr. (2001). The putative oncopretein Bcl-3 induces cyclin D1 to stimulate G1 transition. Mol. Cell. Biol. 21:8428–8436.

    PubMed  Google Scholar 

  45. N. J. Solan, H. Miyoshi, G. D. Bren, and C. V. Paya (2002). RelB cellular regulation and transcriptional activity are regulated by p100. J. Biol. Chem. 277:1405–1418.

    PubMed  Google Scholar 

  46. D. W. Kim, L. Gazourian, S. A. Quadri, R. Romieu-Mourez, D. H. Sherr, and G. E. Sonenshein (2000). The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells. Oncogene 19:5498–5506.

    PubMed  Google Scholar 

  47. E. L. Lagow and D. D. Carson (2002). Synergistic stimulation of MUC1 expression in normal breast epithelial and breast cancer cells by interferon-gamma and tumor necrosis factor-alpha. J. Cell Biochem 86:759–772.

    PubMed  Google Scholar 

  48. V. Deregowski, S. Delhalle, V. Benoit, V. Bours, and M. P. Merville (2002). Identification of cytokine-induced nuclear factor-κB target genes in ovarian and breast cancer cells. Biochem. Pharmacol. 64:873–881.

    PubMed  Google Scholar 

  49. T. S. Finco, J. K. Westwick, J. L. Norris, A. A. Beg, C. J. Der, and A. S. Baldwin Jr. (1997). Oncogenic Ha-Ras-induced signaling activates NF-κB transcriptional activity, which is required for cellular transformation. J. Biol. Chem. 272:24113–24116.

    PubMed  Google Scholar 

  50. H. Jo, R. Zhang, H. Zhang, T. A. McKinsey, J. Shao, R. D. Beauchamp, et al. (2000). NF-κB is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis. Oncogene 19:841–849.

    PubMed  Google Scholar 

  51. S. Pianetti, M. Arsura, R. Romieu-Mourez, R. J. Coffey, and G. E. Sonenshein (2001). Her-2/neu overexpression induces NF-κB via a PI3-kinase/Akt pathway involving calpain-mediated degradation of IκB-alpha that can be inhibited by the tumor suppressor PTEN. Oncogene 20:1287–1299.

    PubMed  Google Scholar 

  52. B. P. Zhou, M. C. Hu, S. A. Miller, Z. Yu, W. Xia, S. Y. Lin, et al. (2000). HER-2/neu blocks tumor necrosis factor-induced apoptosis via the Akt/NF-κB pathway. J. Biol. Chem. 275:8027–8031.

    PubMed  Google Scholar 

  53. L. T. Amundadottir and P. Leder (1998). Signal transduction pathways activated and required for mammary carcinogenesis in response to specific oncogenes. Oncogene 16:737–746.

    PubMed  Google Scholar 

  54. P. Bhat-Nakshatri, C. J. Sweeney, and H. Nakshatri (2002). Identification of signal transduction pathways involved in constitutive NF-κB activation in breast cancer cells. Oncogene 21:2066–2078.

    PubMed  Google Scholar 

  55. D. C. Guttridge, C. Albanese, J. Y. Reuther, R. G. Pestell, and A. S. BaldwinJr. (1999). NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol. Cell. Biol. 19:5785–5799.

    PubMed  Google Scholar 

  56. M. Hinz, D. Krappmann, A. Eichten, A. Heder, C. Scheidereit, and M. Strauss (1999). NF-κB function in growth control: Regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol. Cell. Biol. 19:2690–2698.

    PubMed  Google Scholar 

  57. T. C. Wang, R. D. Cardiff, L. Zukerberg, E. Lees, A. Arnold, and E. V. Schmidt (1994). Mammary hyperplasia and carcinoma in MMTV-cyclin D1 transgenic mice. Nature 369:669–671.

    PubMed  Google Scholar 

  58. Q. Yu, Y. Geng, and P. Sicinski (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021.

    PubMed  Google Scholar 

  59. I. Eto (2000). Molecular cloning and sequence analysis of the promoter region of mouse cyclin D1 gene: implication in phorbol ester-induced tumour promotion. Cell Prolif. 33:167–187.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California

    Yixue Cao & Michael Karin

Authors
  1. Yixue Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Karin
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cao, Y., Karin, M. NF-κB in Mammary Gland Development and Breast Cancer. J Mammary Gland Biol Neoplasia 8, 215–223 (2003). https://doi.org/10.1023/A:1025905008934

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1025905008934

Search

Navigation