Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Cancer Biol Ther. 2010 Sep 15;10(6):600-14. doi: 10.4161/cbt.10.6.12586. Epub 2010 Sep 4.
CXCR4, a chemokine receptor, plays an important role in breast cancer growth, invasion, and metastasis. The transcriptional targets of CXCR4 signaling are not known. Microarray analysis of CXCR4-enriched and CXCR4-low subpopulations of the MDA-MB-231 breast cancer cell line, which has a constitutively active CXCR4 signaling network, revealed differential expression of ∼ 200 genes in the CXCR4-enriched subpopulation. ITF2, upregulated in CXCR4-enriched cells, was investigated further. Expression array datasets of primary breast tumors revealed higher ITF2 expression in estrogen receptor negative tumors, which correlated with reduced progression free and overall survival and suggested its relevance in breast cancer progression. CXCL12, a CXCR4 ligand, increased ITF2 expression in MDA-MB-231 cells. ITF2 is a basic helix-loop-helix transcription factor that controls the epithelial-to-mesenchymal transition and the function of the ID family (inhibitor-of-differentiation) of transcription factors, such as ID2. ID2 promotes differentiation of breast epithelial cells and its reduced expression in breast cancer is associated with an unfavorable prognosis. Both CXCR4 and ITF2 repressed ID2 expression. In xenograft studies, CXCR4-enriched cells formed large tumors and exhibited significantly elevated lung metastasis. Short interfering RNA against ITF2 reduced invasion of the CXCR4-enriched MDA-MB-231 subpopulation, whereas ITF2 overexpression restored the invasive capacity of MDA-MB-231 cells expressing CXCR4shRNA. Furthermore, overexpression of ITF2 in these cells enhanced tumor growth. We propose that ITF2 is one of the CXCR4 targets, which is involved in CXCR4-dependent tumor growth and invasion of breast cancer cells.
趋化因子受体 4（CXCR4）在乳腺癌的生长、侵袭和转移中发挥着重要作用。目前尚不清楚 CXCR4 信号的转录靶标。对 MDA-MB-231 乳腺癌细胞系中 CXCR4 富集和 CXCR4 低表达亚群进行微阵列分析，该细胞系具有组成性激活的 CXCR4 信号网络，结果显示 CXCR4 富集亚群中约有 200 个基因的表达存在差异。进一步研究了在 CXCR4 富集细胞中上调的 ITF2。原发性乳腺癌的表达谱数据集显示，雌激素受体阴性肿瘤中 ITF2 表达较高，与无进展生存期和总生存期缩短相关，提示其与乳腺癌进展相关。CXCR4 的配体 CXCL12 增加了 MDA-MB-231 细胞中 ITF2 的表达。ITF2 是一种碱性螺旋-环-螺旋转录因子，可控制上皮-间充质转化和 ID 家族（分化抑制剂）转录因子的功能，如 ID2。ID2 促进乳腺上皮细胞的分化，其在乳腺癌中的表达降低与预后不良相关。CXCR4 和 ITF2 均抑制 ID2 的表达。在异种移植研究中，CXCR4 富集的细胞形成大肿瘤，并表现出明显升高的肺转移。针对 ITF2 的短发夹 RNA 降低了 CXCR4 富集 MDA-MB-231 亚群的侵袭能力，而 ITF2 的过表达恢复了表达 CXCR4shRNA 的 MDA-MB-231 细胞的侵袭能力。此外，这些细胞中 ITF2 的过表达增强了肿瘤的生长。我们提出，ITF2 是 CXCR4 的靶标之一，它参与了 CXCR4 依赖性的乳腺癌细胞生长和侵袭。
