Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells

Anne T. Mancino, V. Suzanne Klimberg, Matsuo Yamamoto, Stavros C. Manolagas, Etsuko Abe

Research output: Contribution to journalArticlepeer-review

114 Scopus citations


Background. Breast cancer metastasis to bone causes resorption of the mineralized matrix by osteoclasts. Macrophage colony stimulating factor (M-CSF) and receptor activator of the NF-κB ligand (RANKL) are produced by stromal cells and are essential for osteoclast formation. The human breast cancer cell line, MDA-MB-231, reliably forms bone metastases in a murine model and stimulates osteoclast formation in culture. We hypothesized that MDA-MB-231 stimulates osteoclast formation through secretion of M-CSF and/or RANKL. Materials and methods. We cocultured MDA-MB-231 and a bone marrow derived cell line, UAMS-33, and evaluated the expression of M-CSF and RANKL mRNA. Osteoclast formation was assessed using these cells added to hematopoietic cell cultures. Results. MDA-MB-231 exhibited constitutive expression of M-CSF mRNA. As expected, addition of recombinant M-CSF (30 ng/ml) and RANKL (30 ng/ml) to hematopoietic osteoclast precursors supported osteoclast formation, while the addition of soluble RANKL alone or MDA-231 without added RANKL did not. Notably, coculture of MDA-231 with hematopoietic cells and added soluble RANKL stimulated significant osteoclast formation, indicating that MDA-231 served as an effective source for M-CSF. MDA-231 did not express RANKL. However, when cocultured with the murine bone marrow stromal cell line UAMS-33, RANKL expression was significantly increased in the latter cells. MDA-231 also stimulated osteoclast formation in coculture with UAMS-33 and hematopoietic cells. Conclusions. We conclude that MDA-MB-231 increases osteoclast formation by secreting adequate amounts of M-CSF protein and enhancing the expression of RANKL by stromal support cells. The ability to stimulate osteoclasts may explain the ability to metastasize to bone.

Original languageEnglish (US)
Pages (from-to)18-24
Number of pages7
JournalJournal of Surgical Research
Issue number1
StatePublished - 2001
Externally publishedYes


  • Bone metastasis
  • Breast cancer
  • M-CSF
  • MDA-MB-231
  • Osteoclastogenesis

ASJC Scopus subject areas

  • Surgery


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