Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL 60612, USA.
Horm Cancer. 2010 Jun;1(3):127-35. doi: 10.1007/s12672-010-0018-6.
The estrogen receptor (ER) is a major prognostic and therapeutic marker that is expressed in nearly 75% of breast tumors. We have previously shown that the presence of inflammatory mediators can alter the genomic function of the estrogen receptor (ER) in a gene specific manner. In particular, 17β-estradiol (E2) works in combination with the pro-inflammatory cytokines to enhance the expression of a number of pro-survival factors, including the Inhibitor of Apoptosis (IAP) family member, cIAP2. Here we confirm that mRNA and protein levels for cIAP2, but not the related family members cIAP1 and XIAP, are highly up-regulated in MCF-7 breast cancer cells by E2 and cytokines. Similar regulation of cIAP2 is evident in other ER positive but not ER negative cell lines. In agreement with its role as a pro-survival factor, cIAP2 is highly expressed in a subset of invasive breast carcinomas but not in normal breast tissue or ductal carcinoma in situ. Antagonizing IAPs with mimetics of SMAC, which is a known endogenous IAP antagonist, or knockdown of IAPs by siRNA led to greater cell death by TNFα and prevented E2 from promoting cell survival. In addition, a SMAC mimetic reversed TNFα resistance in ER positive breast cancer cells that express high levels of endogenous IAPs. In summary, our findings indicate a new mechanism by which E2 allows breast cancer cells to evade cell death and suggest that an antagonist of IAPs may be a potential therapeutic option for a subset of ER positive breast tumors.
雌激素受体（ER）是一个主要的预后和治疗标志物，几乎在 75%的乳腺癌肿瘤中表达。我们之前已经表明，炎症介质的存在可以以基因特异性的方式改变雌激素受体（ER）的基因组功能。特别是，17β-雌二醇（E2）与促炎细胞因子一起作用，增强了许多促生存因子的表达，包括凋亡抑制剂（IAP）家族成员 cIAP2。在这里，我们证实 cIAP2 的 mRNA 和蛋白水平，但不是相关家族成员 cIAP1 和 XIAP，在 MCF-7 乳腺癌细胞中被 E2 和细胞因子高度上调。在其他 ER 阳性但不是 ER 阴性的细胞系中也可以观察到类似的 cIAP2 调节。与作为促生存因子的作用一致，cIAP2 在一部分浸润性乳腺癌中高度表达，但在正常乳腺组织或导管原位癌中不表达。用 SMAC 的模拟物拮抗 IAPs，SMAC 是一种已知的内源性 IAP 拮抗剂，或用 siRNA 敲低 IAPs，导致 TNFα 引起的细胞死亡增加，并阻止 E2 促进细胞存活。此外，SMAC 模拟物逆转了表达高水平内源性 IAPs 的 ER 阳性乳腺癌细胞对 TNFα 的耐药性。总之，我们的研究结果表明了 E2 使乳腺癌细胞逃避细胞死亡的新机制，并表明 IAPs 的拮抗剂可能是 ER 阳性乳腺癌的一种潜在治疗选择。
