Elsarraj Hanan S, Valdez Kelli E, Hong Yan, Grimm Sandra L, Ricci Lawrence R, Fan Fang, Tawfik Ossama, May Lisa, Cusick Therese, Inciardi Marc, Redick Mark, Gatewood Jason, Winblad Onalisa, Hilsenbeck Susan, Edwards Dean P, Hagan Christy R, Godwin Andrew K, Fabian Carol, Behbod Fariba
Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kansas City, Kansas.
Department of Molecular & Cellular Biology, Pathology & Immunology, Baylor College of Medicine, Houston, Texas.
Cancer Res. 2017 Jul 15;77(14):3802-3813. doi: 10.1158/0008-5472.CAN-16-2794. Epub 2017 May 17.
The beneficial versus detrimental roles of estrogen plus progesterone (E+P) in breast cancer remains controversial. Here we report a beneficial mechanism of E+P treatment in breast cancer cells driven by transcriptional upregulation of the NFκB modulator NEMO, which in turn promotes expression of the tumor suppressor protein promyelocytic leukemia (PML). E+P treatment of patient-derived epithelial cells derived from ductal carcinoma (DCIS) increased secretion of the proinflammatory cytokine IL6. Mechanistic investigations indicated that IL6 upregulation occurred as a result of transcriptional upregulation of , the gene that harbored estrogen receptor (ER) binding sites within its promoter. Accordingly, E+P treatment of breast cancer cells increased ER binding to the promoter, thereby increasing expression, NFκB activation, and IL6 secretion. In two mouse xenograft models of DCIS, we found that RNAi-mediated silencing of increased tumor invasion and progression. This seemingly paradoxical result was linked to NEMO-mediated regulation of NFκB and IL6 secretion, increased phosphorylation of STAT3 on Ser727, and increased expression of PML, a STAT3 transcriptional target. In identifying NEMO as a pivotal transcriptional target of E+P signaling in breast cancer cells, our work offers a mechanistic explanation for the paradoxical antitumorigenic roles of E+P in breast cancer by showing how it upregulates the tumor suppressor protein PML. .
雌激素加孕激素（E+P）在乳腺癌中有益还是有害的作用仍存在争议。在此，我们报告了E+P治疗乳腺癌细胞的一种有益机制，该机制由NFκB调节因子NEMO的转录上调驱动，NEMO进而促进肿瘤抑制蛋白早幼粒细胞白血病（PML）的表达。用E+P处理源自导管癌（DCIS）的患者来源上皮细胞，可增加促炎细胞因子IL6的分泌。机制研究表明，IL6上调是由于其启动子内含有雌激素受体（ER）结合位点的基因转录上调所致。因此，用E+P处理乳腺癌细胞可增加ER与该基因启动子的结合，从而增加其表达、NFκB激活和IL6分泌。在两种DCIS小鼠异种移植模型中，我们发现RNAi介导的该基因沉默会增加肿瘤侵袭和进展。这一看似矛盾的结果与NEMO介导的NFκB调节和IL6分泌、STAT3在Ser727位点的磷酸化增加以及PML（一种STAT3转录靶点）的表达增加有关。在确定NEMO是乳腺癌细胞中E+P信号的关键转录靶点时，我们的工作通过展示E+P如何上调肿瘤抑制蛋白PML，为其在乳腺癌中矛盾的抗肿瘤作用提供了一种机制解释。
