S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways.
S100A7 enhances mammary tumorigenesis through upregulation of inflammatory pathways.
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DOI：
10.1158/0008-5472.can-11-0669
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Ganju RK
中科院分区：
文献类型：
--
作者：
Nasser MW;Qamri Z;Deol YS;Ravi J;Powell CA;Trikha P;Schwendener RA;Bai XF;Shilo K;Zou X;Leone G;Wolf R;Yuspa SH;Ganju RK
S100 A7/Psoriasin是表皮分化复合物的一员，在浸润性ER阴性（ERα-）乳腺癌中广泛过表达。然而，尚未确定S100 A7是否有助于乳腺癌的生长或转移。在这里，我们报告了其表达对影响乳腺癌生长的炎症通路的影响。人S100 A7或其鼠同源物mS 100 a7 a15的过表达增强ERα-乳腺癌细胞中的细胞增殖并上调多种促炎分子。为了检查体内效应，我们产生了具有诱导型mS 100 a7 a15的小鼠（MMTV-mS 100 a7 a15小鼠）。将MVT-1乳腺肿瘤细胞原位移植到这些小鼠的乳腺中增强了肿瘤生长和转移。与未诱导的转基因对照小鼠相比，诱导mS 100 a7 a15的小鼠的乳腺表现出增加的导管增生和参与增殖、信号传导、组织重塑和巨噬细胞募集的分子的表达。此外，从这些小鼠获得的肿瘤和肺组织显示促转移基因表达和肿瘤相关巨噬细胞（TAM）的募集进一步增加。值得注意的是，TAM的体内消耗抑制了mS 100 a7 a15诱导对肿瘤生长和血管生成的影响。此外，可溶性hS 100 A7或mS 100 a7 a15的引入通过活化β受体增强巨噬细胞的趋化性。总之，我们的工作采用了一个强大的新模型系统来证明S100 A7通过激活促炎和转移途径来增强乳腺肿瘤的生长和转移。
S100A7/Psoriasin, a member of the epidermal differentiation complex, is widely overexpressed in invasive ER-negative (ERα-) breast cancers. However, it has not been established whether S100A7 contributes to breast cancer growth or metastasis. Here, we report the consequences of its expression on inflammatory pathways that impact breast cancer growth. Overexpression of human S100A7 or its murine homolog mS100a7a15, enhanced cell proliferation and upregulated various pro-inflammatory molecules in ERα- breast cancer cells. To examine in vivo effects, we generated mice with an inducible form of mS100a7a15 (MMTV-mS100a7a15 mice). Orthotopic implantation of MVT-1 breast tumor cells into the mammary glands of these mice enhanced tumor growth and metastasis. Compared to uninduced transgenic control mice, the mammary glands of mice where mS100a7a15 was induced exhibited increased ductal hyperplasia and expression of molecules involved in proliferation, signaling, tissue remodeling and macrophage recruitment. Furthermore, tumors and lung tissues obtained from these mice showed further increases in pro-metastatic gene expression and recruitment of tumor-associated macrophages (TAMs). Notably, in vivo depletion of TAM inhibited the effects of mS100a7a15 induction on tumor growth and angiogenesis. Further, introduction of soluble hS100A7 or mS100a7a15 enhanced chemotaxis of macrophages via activation of RAGE receptors. In summary, our work employed a powerful new model system to demonstrate that S100A7 enhances breast tumor growth and metastasis by activating proinflammatory and metastatic pathways.