Faculty of Life Sciences, University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
Mol Cancer. 2010 Jun 30;9:171. doi: 10.1186/1476-4598-9-171.
The transcription factor Runx2 has an established role in cancers that metastasize to bone. In metastatic breast cancer cells Runx2 is overexpressed and contributes to the invasive capacity of the cells by regulating the expression of several invasion genes. CBFbeta is a transcriptional co-activator that is recruited to promoters by Runx transcription factors and there is considerable evidence that CBFbeta is essential for the function of Runx factors. However, overexpression of Runx1 can partially rescue the lethal phenotype in CBFbeta-deficient mice, indicating that increased levels of Runx factors can, in some situations, overcome the requirement for CBFbeta. Since Runx2 is overexpressed in metastatic breast cancer cells, and there are no reports of CBFbeta expression in breast cells, we sought to determine whether Runx2 function in these cells was dependent on CBFbeta. Such an interaction might represent a viable target for therapeutic intervention to inhibit bone metastasis.
We show that CBFbeta is expressed in the metastatic breast cancer cells, MDA-MB-231, and that it associates with Runx2. Matrigel invasion assays and RNA interference were used to demonstrate that CBFbeta contributes to the invasive capacity of these cells. Subsequent analysis of Runx2 target genes in MDA-MB-231 cells revealed that CBFbeta is essential for the expression of Osteopontin, Matrixmetalloproteinase-13, Matrixmetalloproteinase-9, and Osteocalcin but not for Galectin-3. Chromatin immunoprecipitation analysis showed that CBFbeta is recruited to both the Osteopontin and the Galectin-3 promoters.
CBFbeta is expressed in metastatic breast cancer cells and is essential for cell invasion. CBFbeta is required for expression of several Runx2-target genes known to be involved in cell invasion. However, whilst CBFbeta is essential for invasion, not all Runx2-target genes require CBFbeta. We conclude that CBFbeta is required for a subset of Runx2-target genes that are sufficient to maintain the invasive phenotype of the cells. These findings suggest that the interaction between Runx2 and CBFbeta might represent a viable target for therapeutic intervention to inhibit bone metastasis.
转录因子 Runx2 在转移到骨骼的癌症中具有既定作用。在转移性乳腺癌细胞中，Runx2 过表达，并通过调节几个侵袭基因的表达来促进细胞的侵袭能力。CBFβ是一种转录共激活因子，它被 Runx 转录因子募集到启动子上，有大量证据表明 CBFβ 对于 Runx 因子的功能是必不可少的。然而，Runx1 的过表达可以部分挽救 CBFβ 缺陷小鼠的致死表型，表明在某些情况下，Runx 因子的水平增加可以克服对 CBFβ 的需求。由于 Runx2 在转移性乳腺癌细胞中过表达，并且在乳腺细胞中没有 CBFβ 表达的报道，我们试图确定这些细胞中的 Runx2 功能是否依赖于 CBFβ。这种相互作用可能是抑制骨转移的治疗干预的一个可行靶点。
我们表明 CBFβ 在转移性乳腺癌细胞 MDA-MB-231 中表达，并与 Runx2 结合。Matrigel 侵袭实验和 RNA 干扰用于证明 CBFβ 有助于这些细胞的侵袭能力。随后对 MDA-MB-231 细胞中的 Runx2 靶基因进行分析表明，CBFβ 对于 Osteopontin、Matrixmetalloproteinase-13、Matrixmetalloproteinase-9 和 Osteocalcin 的表达是必不可少的，但对于 Galectin-3 则不是。染色质免疫沉淀分析表明 CBFβ 被募集到 Osteopontin 和 Galectin-3 启动子上。
CBFβ 在转移性乳腺癌细胞中表达，并对细胞侵袭至关重要。CBFβ 对于几个已知参与细胞侵袭的 Runx2 靶基因的表达是必需的。然而，尽管 CBFβ 对于侵袭是必需的，但并非所有 Runx2 靶基因都需要 CBFβ。我们得出结论，CBFβ 是一组 Runx2 靶基因的子集所必需的，这些基因足以维持细胞的侵袭表型。这些发现表明，Runx2 和 CBFβ 之间的相互作用可能是抑制骨转移的治疗干预的一个可行靶点。
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