Fra-1 Promotes Breast Cancer Chemosensitivity by Driving Cancer Stem Cells from Dormancy
Fra-1 Promotes Breast Cancer Chemosensitivity by Driving Cancer Stem Cells from Dormancy
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DOI：
10.1158/0008-5472.can-11-2536
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发表时间：
2012-07-15
期刊：
影响因子：
11.2
通讯作者：
Xiang, Rong
中科院分区：
文献类型：
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作者：
Lu, Dan;Chen, Si;Xiang, Rong
Fra-1是Fos转录因子家族的成员，在多种癌症中高度表达，在转化、增殖和转移中起重要作用。在这项研究中，我们观察到Fra-1在人II期乳腺癌组织中的表达与相应的临床化疗耐药水平呈负相关。在体外扩展这些发现，我们发现在乳腺肿瘤细胞中敲低Fra-1足以赋予对阿霉素和环磷酰胺的抗性，而增强Fra-1表达可以使这些细胞对化疗敏感。发现富含癌症干细胞的肿瘤细胞侧群与化学抗性相关。在Fra-1敲低的肿瘤细胞系中检测到侧群分数增加。相比之下，Fra-1表达增强与侧群分数降低相关，并且显著地，这一发现在体内重现，其中发现Fra-1表达增强的肿瘤具有钝化生长。Fra-1基因敲低的肿瘤细胞生长更快，体积更大。综上所述，我们的研究结果表明，Fra-1可能是乳腺癌治疗的一个重要预后标志物。Cancer Res; 72（14）; 3451-6.（C）2012年AACR。
Fra-1 is a member of the Fos transcription factor family that is highly expressed in multiple cancers, playing important roles in transformation, proliferation, and metastasis. In this study, we observed an inverse correlation between the expression of Fra-1 in human stage II breast cancer tissues and the corresponding level of clinical chemoresistance. Extending these findings in vitro, we found that knockdown of Fra-1 in breast tumor cells was sufficient to confer resistance to doxorubicin and cyclophosphamide, whereas enhanced Fra-1 expression could render these cells chemosensitive. The tumor cell side population, which is enriched for cancer stem cells, was found to be associated with chemoresistance. Increased side population fractions were detected among tumor cell lines subjected to Fra-1 knockdown. In contrast, enhanced expression of Fra-1 was correlated with a decreased side population fraction, and significantly, this finding was recapitulated in vivo, where tumors with enhanced expression of Fra-1 were found to have blunted growth. Tumor cells subjected to Fra-1 knockdown grew faster and were larger in size. Taken together, our findings suggest that Fra-1 may be an important prognostic marker for breast cancer therapy. Cancer Res; 72(14); 3451-6. (C)2012 AACR.