The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion.
The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion.
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DOI：
10.1158/0008-5472.can-10-0732
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发表时间：
2010-12-15
期刊：
影响因子：
11.2
通讯作者：
Pestell RG
中科院分区：
文献类型：
--
作者：
Liu M;Sakamaki T;Casimiro MC;Willmarth NE;Quong AA;Ju X;Ojeifo J;Jiao X;Yeow WS;Katiyar S;Shirley LA;Joyce D;Lisanti MP;Albanese C;Pestell RG
乳腺肿瘤上皮细胞的核因子-κB在体内肿瘤进展中的作用尚不清楚，因为小鼠的核因子-κB组分是小鼠生存所必需的，也是干扰正常乳腺发育所必需的。由于核因子-κB抑制剂同时阻断肿瘤相关巨噬细胞()和微血管内皮细胞核因子-κB，微血管内皮细胞核因子-κB在体内肿瘤进展中的重要性仍有待确定。因此，我们在ErbB_2乳腺肿瘤中开发了一种针对MEC的可诱导的NF-κB转基因抑制物(IκBαSR)。在成人乳腺上皮中可诱导的抑制NF-κB延迟了新肿瘤的发生和数量。在大小相近的乳腺肿瘤中，和肿瘤新生血管生成均减少。共培养实验表明，MEC NF-κB促进了的招募。全基因组表达和蛋白质组学分析表明，IκBαSR抑制了肿瘤干细胞通路。IκBαSR在转基因肿瘤中抑制乳腺肿瘤干细胞标记物，减少干细胞体外扩增，并抑制体内和体外Nanog和Sox2的表达。乳腺上皮细胞NF-κB参与乳腺肿瘤的发生。我们发现，NF-κB有助于乳腺肿瘤干细胞的扩增，以及促进和血管生成的异型信号，这些过程可能有助于依赖于NF-κB的乳腺肿瘤的发生。
The role of mammary tumor epithelial cell (MEC) NF-κB in tumor progression in vivo is unknown as murine NF-κB components and kinases are either 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. Co-culture experiments demonstrated MEC NF-κB enhanced TAM recruitment. Genome wide expression and proteomic analysis demonstrated 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. Mammary epithelial cell NF-κB contributes to mammary tumorigenesis. As we show 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.