Osteoblast-related transcription factors Runx2 (Cbfa1/AML3) and MSX2 mediate the expression of bone sialoprotein in human metastatic breast cancer cells.
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.
Department of Orthopaedic Surgery, Boston University Medical Center, Boston, Massachusetts 02118, USA. gbarnes@bu.edu
George L
GL
Barnes
Amjad
A
Javed
Sylvan M
SM
Waller
Mohammad H
MH
Kamal
Kerri E
KE
Hebert
Mohammad Q
MQ
Hassan
Akeila
A
Bellahcene
Andre J
AJ
Van Wijnen
Marian F
MF
Young
Jane B
JB
Lian
Gary S
GS
Stein
Louis C
LC
Gerstenfeld
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D058574:Integrin-Binding Sialoprotein; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins; D011401:Promoter Regions, Genetic; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
D050659:Core Binding Factor Alpha 1 Subunit; D050657:Core Binding Factor alpha Subunits; C100596:DLX5 protein, human; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C546871:IBSP protein, human; D058574:Integrin-Binding Sialoprotein; C084119:MSX2 protein; D009363:Neoplasm Proteins; D012795:Sialoglycoproteins; D014157:Transcription Factors