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

被引:42
作者
Bowie, ML
Dietze, EC
Delrow, J
Bean, GR
Troch, MM
Marjoram, RJ
Seewaldt, VL
机构
[1] Duke Univ, Med Ctr, Div Med Oncol, Durham, NC 27710 USA
[2] Fred Hutchinson Canc Res Ctr, Seattle, WA 98120 USA
[3] Duke Univ, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA
关键词
IRF-1; tamoxifen; CBP; breast cancer;
D O I
10.1038/sj.onc.1208120
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 muM 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 muM 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 muM Tam resulted in recruitment of CBP to the gamma-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.
引用
收藏
页码:8743 / 8755
页数:13
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