Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells
bone sialoprotein; Runx2; breast cancer; osteoblast
Abstract :
[en] 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 by 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.
Bellahcene, Akeila ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Labo de recherche sur les métastases
van Wijnen, A. J.
Young, M. F.
Lian, J. B.
Stein, G. S.
Gerstenfeld, L. C.
Language :
English
Title :
Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells
Publication date :
15 May 2003
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
Amer Assoc Cancer Research, Birmingham, United States - Alabama
Volume :
63
Issue :
10
Pages :
2631-2637
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
American Cancer Society Grant IRG-72-001-24-URG NIH - National Institutes of Health [US-MD] Department of Orthopaedic Surgery, Boston University Medical Center
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