Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Cancer Res. 2010 Dec 15;70(24):10464-73. doi: 10.1158/0008-5472.CAN-10-0732.
The role of mammary epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown, as murine NF-κB components and kinases either are required for murine survival or interfere with normal mammary gland development. As NF-κB inhibitors block both tumor-associated macrophages (TAM) and MEC NF-κB, the importance of MEC NF-κB to tumor progression in vivo remained to be determined. Herein, an MEC-targeted inducible transgenic inhibitor of NF-κB (IκBαSR) was developed in ErbB2 mammary oncomice. Inducible suppression of NF-κB in the adult mammary epithelium delayed the onset and number of new tumors. Within similar sized breast tumors, TAM and tumor neoangiogenesis was reduced. Coculture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome-wide expression and proteomic analysis showed that IκBαSR inhibited tumor stem cell pathways. IκBαSR inhibited breast tumor stem cell markers in transgenic tumors, reduced stem cell expansion in vitro, and repressed expression of Nanog and Sox2 in vivo and in vitro. MEC NF-κB contributes to mammary tumorigenesis. As we show that NF-κB contributes to expansion of breast tumor stem cells and heterotypic signals that enhance TAM and vasculogenesis, these processes may contribute to NF-κB-dependent mammary tumorigenesis.
乳腺上皮细胞 (MEC) NF-κB 在体内肿瘤进展中的作用尚不清楚，因为鼠类 NF-κB 成分和激酶要么是鼠类生存所必需的，要么会干扰正常乳腺发育。由于 NF-κB 抑制剂既能阻断肿瘤相关巨噬细胞 (TAM) 又能阻断 MEC NF-κB，因此 MEC NF-κB 对体内肿瘤进展的重要性仍有待确定。在此，在 ErbB2 乳腺致癌小鼠中开发了一种 MEC 靶向诱导型 NF-κB 抑制剂 (IκBαSR)。成年乳腺上皮细胞中 NF-κB 的诱导性抑制可延迟新肿瘤的发生和数量。在类似大小的乳腺肿瘤中，TAM 和肿瘤新生血管形成减少。共培养实验表明，MEC NF-κB 增强了 TAM 的募集。全基因组表达和蛋白质组学分析表明，IκBαSR 抑制了肿瘤干细胞途径。IκBαSR 抑制了转基因肿瘤中的乳腺肿瘤干细胞标志物，减少了体外肿瘤干细胞的扩增，并抑制了体内和体外 Nanog 和 Sox2 的表达。MEC NF-κB 有助于乳腺肿瘤发生。正如我们所表明的，NF-κB 有助于乳腺肿瘤干细胞的扩增以及增强 TAM 和血管生成的异质信号，这些过程可能有助于 NF-κB 依赖性乳腺肿瘤发生。
