Breast cancer cells interact with osteoblasts to support osteoclast formation.
Breast cancers commonly cause osteolytic metastases in bone, a process that is dependent upon osteoclast-mediated bone resorption. Recently the osteoclast differentiation factor (ODF), better termed RANKL (receptor activator of NF-kappaB ligand), expressed by osteoblasts has been cloned as well as its cognate signaling receptor, receptor activator of NFkappaB (RANK), and a secreted decoy receptor osteoprotegerin (OPG) that limits RANKL's biological action. We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK. MCF-7, MDA-MB-231, and T47D cells did not act as surrogate osteoblasts to support osteoclast formation in coculture experiments, a result consistent with the fact that they do not express RANKL. When MCF-7 cells overexpressing PTH-related protein (PTHrP) were added to cocultures of murine osteoblasts and hematopoietic cells, osteoclast formation resulted without the addition of any osteotropic agents; cocultures with MCF-7 or MCF-7 cells transfected with pcDNAIneo required exogenous agents for osteoclast formation. When MCF-7 cells overexpressing PTHrP were cultured with murine osteoblasts, osteoblastic RANKL messenger RNA (mRNA) levels were enhanced and osteoblastic OPG mRNA levels diminished; MCF-7 parental cells had no effect on RANKL or OPG mRNA levels when cultured with osteoblastic cells. Using a murine model of breast cancer metastasis to bone, we established that MCF-7 cells that overexpress PTHrP caused significantly more bone metastases, which were associated with increased osteoclast formation, elevated plasma PTHrP concentrations and hypercalcaemia compared with parental or empty vector controls.
Thomas
R J
RJ
St. Vincent's Institute of Medical Research and The University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Guise
T A
TA
Yin
J J
JJ
Elliott
J
J
Horwood
N J
NJ
Martin
T J
TJ
Gillespie
M T
MT
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002455:Cell Division / Q000502:physiology; D018920:Coculture Techniques; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000378:metabolism / Q000502:physiology*; D010010:Osteoclasts / Q000166:cytology*; D010014:Osteolysis / Q000503:physiopathology; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins / Q000378:metabolism / Q000502:physiology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D011506:Proteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505687:Tnfrsf11a protein, mouse; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse