Fidelity of Runx2 activity in breast cancer cells is required for the generation of metastases-associated osteolytic disease.
The osteolytic bone destruction associated with breast cancer skeletal metastases represents a serious and incurable clinical condition. However, the molecular mechanisms regulating tumor cell expression of factors involved in the generation of osteolytic disease remain elusive. We demonstrated recently that breast cancer cells express the Runx2 transcription factor, essential for bone formation and a regulator of skeletal homeostasis. Our experimental results demonstrate that perturbation of Runx2 regulatory function in tumor cells abolishes their ability to form osteolytic lesions in vivo. In vitro, we show that breast cancer cells inhibit osteoblast differentiation while concurrently enhancing osteoclast differentiation in marrow stromal cell cultures. Disruption of Runx2 activity abrogates both of these cancer cell-mediated effects on bone cells. These results demonstrate that Runx2 expression in breast cancer cells provides a molecular phenotype that enables the interactions between tumor cells and the bone microenvironment that lead to osteolytic disease.
Barnes
George L
GL
Department of Orthopaedic Surgery, Boston University Medical Center, Massachusetts 02118, USA. gbarnes@bu.edu
Hebert
Kerri E
KE
Kamal
Mohammad
M
Javed
Amjad
A
Einhorn
Thomas A
TA
Lian
Jane B
JB
Stein
Gary S
GS
Gerstenfeld
Louis C
LC
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D050659:Core Binding Factor Alpha 1 Subunit; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*
D050659:Core Binding Factor Alpha 1 Subunit; D016207:Cytokines; D009363:Neoplasm Proteins; D014157:Transcription Factors