Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
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发表时间：
2003-05
期刊：
影响因子：
11.2
通讯作者：
G. Barnes;A. Javed;Sylvan M Waller;M. Kamal;Kerri E Hebert;Mohammad Q. Hassan;A. Bellahcène;A. V.
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文献类型：
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作者：
G. Barnes;A. Javed;Sylvan M Waller;M. Kamal;Kerri E Hebert;Mohammad Q. Hassan;A. Bellahcène;A. V.
已知人类乳腺癌优先转移到骨骼部位，然而，介导特定类型癌症的骨骼偏好（正向异性）的机制仍然知之甚少。骨涎蛋白（bone saloprotein， BSP）表达与乳腺癌骨转移有显著的临床相关性。我们的实验室以及其他实验室提出了骨骼选择性转移和相关疾病可能归因于转移癌细胞对骨骼细胞表型的模仿的概念。我们假设乳腺癌细胞表达骨骼细胞类型的表型特性，包括BSP作为该表型的一个组成部分，是骨细胞基因表达的一个或多个中心转录调节因子的异位表达或活性的结果。为了验证这一假设，我们研究了调节bsp在人类乳腺癌细胞系中表达的分子机制，这些细胞系具有先前表征的转移潜力。我们的研究结果表明，大多数远端bsp启动子序列抑制bsp在癌细胞中的表达，并且大多数启动子活性位于bsp启动子的近端-110 bp。在这个区域，我们发现了一个假定的Runx结合元件，为骨骼基因激活机制提供了基础。我们的研究结果表明，Runx2在乳腺癌细胞中异位表达，并且Runx2的一个亚型可以激活这些细胞中的bsp表达。此外，我们观察到bsp的表达还受同源结构域因子Msx2的调节，Msx2是另一种成骨相关基因的调节因子。因此，这是第一个在人乳腺癌细胞中表达成骨细胞相关转录因子的报告，并提供了一个可能解释人乳腺癌细胞优先转移到骨的成骨表型的机制的组成部分。
Human breast cancers are known to preferentially metastasize to skeletal sites, however, the mechanisms that mediate the skeletal preference (orthotropism) of specific types of cancers remains poorly understood. There is a significant clinical correlation between the expression of bone sialoprotein (BSP) and skeletal metastasis of breast cancers. Our laboratory, as well as others, have proposed the concept that skeletal selective metastasis and associated disease may be attributable to a mimicry of skeletal cellular phenotypes by metastasizing cancer cells. We hypothesize that breast cancer cell expression of phenotypic properties of skeletal cell types, including BSP as one component of that phenotype, is the result of ectopic expression or activity of one or more central transcriptional regulators of bone cell gene expression. To test this hypothesis, we examined the molecular mechanisms that regulate bsp expression in human breast cancer cell lines with previously characterized metastatic potentials. Our results demonstrate that the majority of the distal bsp promoter sequences act to repress BSP expression in cancer cells and that most of the promoter activity resides in the proximal -110 bp of the bsp promoter. In this region, we identified a putative Runx binding element providing a basis for a mechanism for skeletal gene activation. Our results demonstrate that Runx2 is ectopically expressed in breast cancer cells and that one isoform of Runx2 can activate bsp expression in these cells. In addition, we observe that bsp expression is additionally regulated by the homeodomain factor Msx2, another regulator of osteoblast-associated genes. Thus, this is the first report of osteoblast-related transcription factors being expressed in human breast cancer cells and provides a component of a mechanism that may explain the osteoblastic phenotype of human breast cancer cells that preferentially metastasize to bone.