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Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.

Abstract：

: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.

journal_name

Cancer Res

journal_title

Cancer research

authors

Barnes GL,Javed A,Waller SM,Kamal MH,Hebert KE,Hassan MQ,Bellahcene A,Van Wijnen AJ,Young MF,Lian JB,Stein GS,Gerstenfeld LC

subject

Has Abstract

pub_date

2003-05-15 00:00:00

pages

2631-7

issue

eissn

0008-5472

issn

1538-7445

journal_volume

pub_type

杂志文章

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Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.