NF-κB in Mammary Gland Development and Breast Cancer

  • Yixue Cao
  • Michael Karin
Article

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.

NF-κIKKα mammary gland development cyclin D1 breast cancer 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. 1.
    S. Ghosh and M. Karin (2002). Missing pieces in the NF-κB puzzle. Cell 109(Suppl):S81-S96.PubMedGoogle Scholar
  2. 2.
    M. Karin and A. Lin (2002). NF-κB at the crossroads of life and death. Nat. Immunol. 3:221–227.PubMedGoogle Scholar
  3. 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.PubMedGoogle Scholar
  4. 4.
    M. J. May and S. Ghosh (1997). Rel/NF-κB and IκB proteins: An overview. Semin. Cancer Biol. 8:63–73.PubMedGoogle Scholar
  5. 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.PubMedGoogle Scholar
  6. 6.
    M. Karin and Y. Ben-Neriah (2000). Phosphorylation meets ubiquitination: The control of NF-[κ]B activity. Annu. Rev. Immunol. 18:621–663.PubMedGoogle Scholar
  7. 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.PubMedGoogle Scholar
  8. 8.
    H. Pahl (1999). Activators and target genes of Rel/NF-κB transcription factors. Oncogene 18: 6853–6866.PubMedGoogle Scholar
  9. 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. 10.
    B. Rayet and C. Gelinas (1999). Aberrant rel/nfkb genes and activity in human cancer. Oncogene 18:6938–6947.PubMedGoogle Scholar
  11. 11.
    T. Gilmore, M. Koedood, K. Piffat, and D. White (1996). Rel/NF-κB/IκB proteins and cancer. Oncogene 13: 1367–1378.PubMedGoogle Scholar
  12. 12.
    L. Hennighausen and G. W. Robinson (2001). Signaling pathways in mammary gland development. Dev. Cell 1:467–475.PubMedGoogle Scholar
  13. 13.
    L. Hennighausen and G. W. Robinson (1998). Think globally, act locally: The making of a mouse mammary gland. Genes Dev. 12: 449–455.PubMedGoogle Scholar
  14. 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.PubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.PubMedGoogle Scholar
  20. 20.
    G. Luo and L. Yu-Lee (2000). Stat5b inhibits NF-kB-mediated signaling. Mol. Endocrinol. 14: 114–123.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. 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.PubMedGoogle Scholar
  25. 25.
    L. Varela and M. Ip (1996). Tumor necrosis factor-alpha:A multifunctional regulator of mammary gland development. Endocrinology 137:4915–4924.PubMedGoogle Scholar
  26. 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.PubMedGoogle Scholar
  27. 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.PubMedGoogle Scholar
  28. 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.PubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.PubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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.PubMedGoogle Scholar
  38. 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.PubMedGoogle Scholar
  39. 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.PubMedGoogle Scholar
  40. 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.PubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 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.PubMedGoogle Scholar
  43. 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.PubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 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.PubMedGoogle Scholar
  46. 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.PubMedGoogle Scholar
  47. 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.PubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedGoogle Scholar
  53. 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.PubMedGoogle Scholar
  54. 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.PubMedGoogle Scholar
  55. 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.PubMedGoogle Scholar
  56. 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.PubMedGoogle Scholar
  57. 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.PubMedGoogle Scholar
  58. 58.
    Q. Yu, Y. Geng, and P. Sicinski (2001). Specific protection against breast cancers by cyclin D1 ablation. Nature 411:1017–1021.PubMedGoogle Scholar
  59. 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.PubMedGoogle Scholar

Copyright information

© Plenum Publishing Corporation 2003

Authors and Affiliations

  • Yixue Cao
    • 1
  • Michael Karin
    • 1
  1. 1.Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of MedicineUniversity of CaliforniaSan Diego, La Jolla

Personalised recommendations