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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.

Original publication

DOI

10.1210/endo.140.10.7037

Type

Journal article

Journal

Endocrinology

Publication Date

10/1999

Volume

140

Pages

4451 - 4458

Keywords

Animals, Carrier Proteins, Cell Division, Coculture Techniques, Female, Glycoproteins, Male, Mammary Neoplasms, Animal, Membrane Glycoproteins, Mice, Mice, Inbred C57BL, Osteoblasts, Osteoclasts, Osteolysis, Osteoprotegerin, Parathyroid Hormone-Related Protein, Proteins, RANK Ligand, RNA, Messenger, Receptor Activator of Nuclear Factor-kappa B, Receptors, Cytoplasmic and Nuclear, Receptors, Tumor Necrosis Factor, Tumor Cells, Cultured