Molecular mechanisms of breast cancer metastases to bone.

Theresa A. Guise, Wende M. Kozlow, Ailleen Heras-Herzig, Susan S. Padalecki, Juan Juan Yin, John M. Chirgwin

Research output: Contribution to journalReview articlepeer-review

146 Scopus citations


Bone metastases lead to hypercalcemia, bone pain, fractures, and nerve compression. They cause increased morbidity and mortality in patients with advanced breast cancer. Animal models reproduce many of the features seen in patients with breast cancer and permit identification of tumor- and bone-derived factors important in skeletal metastasis. These factors provide novel targets for therapeutic interventions. Specific tumor-bone molecular interactions mediated by these factors drive a vicious cycle that perpetuates skeletal metastases. In breast cancer, osteolytic metastases are most common, but mixed and osteoblastic metastases occur in a significant number of patients. Parathyroid hormone-related protein is a common osteolytic factor, and vascular endothelial growth factor and interleukins 8 and 11 also contribute. Osteoblastic metastases can be caused by tumor-secreted endothelin-1 (ET-1), but there are a variety of other potential osteoblastic factors. Stimulation of osteoblasts can paradoxically increase osteoclast function, as bone-synthesizing osteoblasts are the main regulators of bone-destroying osteoclasts. Coexpression of osteolytic and osteoblastic factors can thus produce mixed metastases or increased osteolysis. Cancer treatments, especially sex steroid deprivation therapies, stimulate bone loss. Bone resorption results in the release of bone growth factors, which may unintentionally increase the formation of bone metastases by activating the vicious cycle. Clinically approved bisphosphonates prevent bone resorption and reduce the release of bone growth factors. Parathyroid hormone-related protein-neutralizing antibody, inhibitors of the receptor activator of nuclear factor-kB ligand pathway, and ET-1 receptor antagonists are in clinical trials. These agents act on bone cells rather than tumor cells. Recent experiments identify new potential targets for prevention of bone metastases.

Original languageEnglish (US)
Pages (from-to)S46-53
JournalClinical breast cancer
Volume5 Suppl
Issue number2
StatePublished - Feb 2005
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'Molecular mechanisms of breast cancer metastases to bone.'. Together they form a unique fingerprint.

Cite this