Bowie Michelle L, Dietze Eric C, Delrow Jeffery, Bean Gregory R, Troch Michelle M, Marjoram Robin J, Seewaldt Victoria L
Division of Medical Oncology, Duke University, Durham, NC 27710, USA.
Oncogene. 2004 Nov 18;23(54):8743-55. doi: 10.1038/sj.onc.1208120.
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 microM 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 microM 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 microM 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.
与雌激素受体阳性（ER(+)）乳腺癌不同，正常人类乳腺上皮细胞（HMECs）通常细胞核内雌激素受体（ER）表达水平较低（ER缺乏）。我们之前证明，1.0微摩尔他莫昔芬（Tam）通过一条快速的“非经典”信号通路促进急性损伤的ER缺乏的HMECs凋亡。干扰素调节因子-1（IRF-1）是信号转导和转录激活因子-1转录调控的一个靶点，已被证明在DNA损伤后可促进凋亡。在此我们表明，1.0微摩尔Tam通过诱导IRF-1和激活半胱天冬酶-1/3促进急性损伤的ER缺乏的HMECs凋亡。用1.0微摩尔Tam处理急性损伤的HMEC-E6细胞导致CBP募集到IRF-1启动子的γ-干扰素激活序列元件，诱导IRF-1，并依次激活半胱天冬酶-1和-3。Tam的作用被针对IRF-1的小干扰RNA（siRNA）表达和半胱天冬酶-1抑制剂阻断。这些数据表明，Tam通过一条新的IRF-1介导的信号通路诱导HMEC-E6细胞凋亡，该通路导致半胱天冬酶-1和-3激活。
