IRF-1 Promotes Apoptosis in p53-damaged Basal-type Human Mammary Epithelial Cells: A Model for Early Basal-type Mammary Carcinogenesis

  • Michelle L. Bowie
  • Catherine Ibarra
  • Victoria L. Seewalt
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 617)


Mammary gland homeostasis is regulated by both endogenous and exogenous signals, creating a balance between proliferation and apoptosis. It is thought that breast cancer develops from the acquisition of multiple genetic changes. The function of tumor suppressor p53 is fequently lost in cancers; however, not all cells that lose p53 progress to become invasive cancer. We have developed a model of early mammary carcinogenesis to investigate some of the internal and external signaling pathways that target the elimination ot normal basal-type human mammary epithelial cells (HMECs) that acutely acquire p53-damage. Here, we show that both tamoxifen (Tam) and three-dimensional prepared extracellular matrix culture (3-D rECM) induce apoptosis in HMEC cells with acute loss of p53 [*p53(-) HMECs] through induction of interferon regulatory factor-1 (IRF-1). Tam and rECM signaling in *p53(-) HMECs (1) promotes the recruitment of a STAT1/CBP complex to the IRF-1 promoter, (2) upregulates IRF-1, (3) activates caspase-1 and -3, and (4) induces apoptosis. Suppression of IRF-1 with siRNA oligos inhibited both Tam- and rECM-induced apoptosis. These observations demonstrate that IRF-1 plays a critical role in eliminating p53-damaged cells, and may play a more global role in mammary gland homeostasis.


Mammary Epithelial Cell Human Mammary Epithelial Cell Normal Human Mammary Epithelial Cell Basal Cytokeratin Young African American Woman 
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  1. 1.
    Borresen-Dale AL (2003) TP53 and breast cancer. Hum Mutat 21: 292–300.PubMedCrossRefGoogle Scholar
  2. 2.
    Perou CM, Sorlie T, Eisen MB, et al. (2000) Molecular portraits of human breast tumours. Nature 406: 747–752.PubMedCrossRefGoogle Scholar
  3. 3.
    Foulkes WD, Stefansson IM, Chappuis PO, et al. (2003) Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 95: 1482–1485.PubMedGoogle Scholar
  4. 4.
    Miyamoto M, Fujita T, Kimura Y, et al. (1988) Regulated expression of a gene encoding a nuclear factor, IRF-1, specifically binds to IFN-beta gene regulatory elements. Cell 54: 903–913.PubMedCrossRefGoogle Scholar
  5. 5.
    Taniguchi T, Ogasawara K, Takaoka A, et al. (2001) IRF family of transcription factors as regulators of host defense. Annu Rev Immunol 19: 623–655.PubMedCrossRefGoogle Scholar
  6. 6.
    Chatterjee-Kishore M, Kishore R, Hicklin DJ, et al. (1998) Different requirements for signal transducer and activator of transcription 1alpha and interferon regulatory factor 1 in the regulation of low molecular mass polypeptide 2 and transporter associated with antigen processing 1 gene expression. J. Biol. Chem. 273: 16177–16183.PubMedCrossRefGoogle Scholar
  7. 7.
    Porta C, Hadj-Slimane R, Nejmeddine M, et al. (2005) Interferons alpha and gamma induce p53-dependent and p53-independent apoptosis, respectively. Oncogene 24: 605–615.PubMedCrossRefGoogle Scholar
  8. 8.
    Tamura T, Ishihara M, Lamphier MS, et al. (1995) An Irf-1-dependent pathway of DNA damage-induced apoptosis in mitogen-activated T-lymphocytes. Nature 376: 596–599.PubMedCrossRefGoogle Scholar
  9. 9.
    Hoshiya Y, Gupta V, Kawakubo H, et al. (2003) Mullerian inhibiting substance promotes interferon gamma-induced gene expression and apoptosis in breast cancer cells. J Biol Chem 278: 51703–51712.PubMedCrossRefGoogle Scholar
  10. 10.
    Kim PK, Armstrong M, Liu Y, et al. (2004) IRF-1 expression induces apoptosis and inhibits tumor growth in mouse mammary cancer cells in vitro and in vivo. Oncogene 23: 1125–1135.PubMedCrossRefGoogle Scholar
  11. 11.
    Pizzoferrato E, Liu Y, Gambotto A, et al. (2004) Ectopic expression of interferon regulatory factor-1 promotes human breast cancer cell death and results in reduced expression of survivin. Cancer Res 64: 8381–8388.PubMedCrossRefGoogle Scholar
  12. 12.
    Bouker KB, Skaar TC, Fernandez DR, et al. (2004) Interferon regulatory factor-1 mediates the proapoptotic but not cell cycle arrest effects of the steroidal antiestrogen ICI 182, 780 (faslodex, fulvestrant). Cancer Res 64: 4030–4039.PubMedCrossRefGoogle Scholar
  13. 13.
    Nozawa H, Oda E, Nakao K, et al. (1999) Loss of transcription factor IRF-1 affects tumor susceptibility in mice carrying the Ha-ras transgene or nullizygosity for p53. Genes Dev 13: 1240–1245.PubMedCrossRefGoogle Scholar
  14. 14.
    Doherty GM, Boucher L, Sorenson K, et al. (2001) Interferon regulatory factor expression in human breast cancer. Ann Surg 233: 623–629.PubMedCrossRefGoogle Scholar
  15. 15.
    Connett JM, Badri L, Giordano TJ, et al. (2005) Interferon regulatory factor 1 (IRF-1) and IRF-2 expression in breast cancer tissue microarrays. J Interferon Cytokine Res 25: 587–594.PubMedCrossRefGoogle Scholar
  16. 16.
    Bowie ML, Dietze EC, Delrow J, et al. (2004) Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells. Oncogene 23: 8743–8755.PubMedCrossRefGoogle Scholar
  17. 17.
    Dietze EC, Caldwell LE, Grupin SL, et al. (2001) Tamoxifen but not 4-hydroxytamoxifen initiates apoptosis in p53(−) normal human mammary epithelial cells by inducing mitochondrial depolarization. J Biol Chem 276: 5384–5394.PubMedCrossRefGoogle Scholar
  18. 18.
    Dietze EC, Troch MM, Bean GR, et al. (2004) Tamoxifen and tamoxifen ethyl bromide induce apoptosis in acutely damaged mammary epithelial cells through modulation of AKT activity. Oncogene 23: 3851–3862.PubMedCrossRefGoogle Scholar
  19. 19.
    Gu Z, Lee RY, Skaar TC, et al. (2002) Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182, 780). Cancer Res 62: 3428–3437.PubMedGoogle Scholar
  20. 20.
    Seewaldt VL, Mrozek K, Dietze EC, et al. (2001) Human papillomavirus type 16 E6 inactivation of p53 in normal human mammary epithelial cells promotes tamoxifen-mediated apoptosis. Cancer Res 61: 616–624.PubMedGoogle Scholar
  21. 21.
    Seewaldt VL, Mrozek K, Sigle R, Dietze EC, Heine K, Hockenbery DM, Hobbs KB, Caldwell LE (2001) Suppression of p53 function in normal human mammary epithelial cells increases sensitivity to extracellular matrix-induced apoptosis. J Cell Biol 155: 471–486.PubMedCrossRefGoogle Scholar
  22. 22.
    Roskelley CD, Desprez PY, Bissell MJ (1994) Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc Natl Acad Sci USA 91: 12378–12382.PubMedCrossRefGoogle Scholar
  23. 23.
    Dietze EC, Bowie ML, Mrozek K, et al. (2005) CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5. J Cell Sci 118: 5005–5022.PubMedCrossRefGoogle Scholar
  24. 24.
    Horvai AE, Xu L, Korzus E, et al. (1997) Nuclear integration of JAK/STAT and Ras/AP-1 signaling by CBP and p300. Proc Natl Acad Sci USA 94: 1074–1079.PubMedCrossRefGoogle Scholar
  25. 25.
    Karlsen AE, Pavlovic D, Nielsen K, et al. (2000) Interferon-gamma induces interleukin-1 converting enzyme expression in pancreatic islets by an interferon regulatory factor-1-dependent mechanism. J Clin Endocrinol Metab 85: 830–836.PubMedCrossRefGoogle Scholar
  26. 26.
    Farrelly N, Lee YJ, Oliver J, et al. (1999) Extracellular matrix regulates apoptosis in mammary epithelium through a control on insulin signaling. J Cell Biol 144: 1337–348.PubMedCrossRefGoogle Scholar
  27. 27.
    Stupack DG, Cheresh DA (2002) Get a ligand, get a life: integrins, signaling and cell survival. J Cell Sci 115: 3729–3738.PubMedCrossRefGoogle Scholar
  28. 28.
    Bouker KB, Skaar TC, Riggins RB, et al. (2005) Interferon regulatory factor-1 (IRF-1) exhibits tumor suppressor activities in breast cancer associated with caspase activation and induction of apoptosis. Carcinogenesis 26: 1527–1535.PubMedCrossRefGoogle Scholar

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© Springer 2008

Authors and Affiliations

  • Michelle L. Bowie
  • Catherine Ibarra
  • Victoria L. Seewalt

There are no affiliations available

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