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  • Original Paper
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Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

Oncogene volume 23, pages 8743–8755 (2004)Cite this article

Abstract

Unlike estrogen receptor-positive (ER(+)) breast cancers, normal human mammary epithelial cells (HMECs) typically express low nuclear levels of ER (ER poor). We previously demonstrated that 1.0 μ M tamoxifen (Tam) promotes apoptosis in acutely damaged ER-poor HMECs through a rapid, ‘nonclassic’ signaling pathway. Interferon-regulatory factor-1 (IRF-1), a target of signal transducer and activator of transcription-1 transcriptional regulation, has been shown to promote apoptosis following DNA damage. Here we show that 1.0 μ M Tam promotes apoptosis in acutely damaged ER-poor HMECs through IRF-1 induction and caspase-1/3 activation. Treatment of acutely damaged HMEC-E6 cells with 1.0 μ M Tam resulted in recruitment of CBP to the γ-IFN-activated sequence element of the IRF-1 promoter, induction of IRF-1, and sequential activation of caspase-1 and -3. The effects of Tam were blocked by expression of siRNA directed against IRF-1 and caspase-1 inhibitors. These data indicate that Tam induces apoptosis in HMEC-E6 cells through a novel IRF-1-mediated signaling pathway that results in activated caspase-1 and -3.

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Acknowledgements

This work is supported by NIH/NCI grants 2P30CA14236–26 (VLS, ECD), R01CA88799 (VLS), R01CA984441 (VLS), NIH/NIDDK grant 2P30DK 35816-11 (VLS), DAMD-98-1-851 and DAMD-010919 (VLS), American Cancer Society Award CCE-99898 (VLS), a V-Foundation Award (VLS), a Susan G Komen Breast Cancer Award (VLS, ECD), and a Charlotte Geyer Award (VLS). The authors gratefully acknowledge Martha Stamfer's gift of normal human mammary epithelial cells and D Galloway for the LXSN16E6 retroviral vector containing the HPV-16E6 coding sequence.

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  1. Division of Medical Oncology, Duke University, Durham, 27710, NC, USA

    Michelle L Bowie, Eric C Dietze, Gregory R Bean, Michelle M Troch, Robin J Marjoram & Victoria L Seewaldt

  2. Fred Hutchinson Cancer Research Center, Seattle, 98120, WA, USA

    Jeffery Delrow

  3. Department of Pharmacology and Cancer Biology, Duke University, Durham, 27710, NC, USA

    Victoria L Seewaldt

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Correspondence to Victoria L Seewaldt.

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Bowie, M., Dietze, E., Delrow, J. et al. Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells. Oncogene 23, 8743–8755 (2004). https://doi.org/10.1038/sj.onc.1208120

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