Molecular mechanism of osteolytic bone metastases

Abstract

BACKGROUND. Breast carcinoma commonly metastasizes to the skeleton in patients with advanced disease to cause bone destruction and the associated pain, hypercalcemia, fracture, and nerve-compression syndromes. In this scenario, the bone destruction is mediated by the osteoclast. Tumor-produced parathyroid hormone-related protein (PTHrP), a known stimulator of osteoclastic bone resorption, is a major mediator of the osteolytic process. Transforming growth factor β (TGFβ), which is abundant in bone matrix and is released as a consequence of osteoclastic bone resorption, may promote breast carcinoma osteolysis by stimulating PTHrP production by tumor cells. METHODS. Stable breast carcinoma MDA-MB-231 cell lines were constructed that expressed mutant TGFβ receptors, Smad proteins, or estrogen receptor (ER)-α and were used to determine the role of TGFβ in modulating tumor production of PTHrP. These stable cell lines were applied to a mouse model of human breast carcinoma metastases to the bone to dissect the molecular mechanisms responsible for osteolytic bone metastases. RESULTS. TGFβ promoted the development and progression of osteolytic bone metastases by inducing tumor production of PTHrP, the effect of which was mediated through the Smad signaling pathway. PTHrP stimulated osteoclastic bone resorption by increasing osteoblast production of the receptor activator of nuclear factor κ B (RANK) ligand and decreasing osteoblast production of osteoprotegerin (OPG). A constitutively active ER-α mutation (Tyr537Asn), identified from a human bone metastases, when it was expressed in human breast carcinoma cells, caused increased production of PTHrP. TGFβ significantly enhanced the ER-α- mediated transcriptional activity induced by ER-α (Tyr537Asn), and this resulted in further stimulation of PTHrP production. CONCLUSIONS. These data indicate a central role for TGFβ in the pathogenesis of osteolytic bone metastases from breast carcinoma by 1) the induction of PTHrP through the Smad signaling pathway and 2) the potentiation of ER-α-mediated transcription induced by a constitutively active ER-α. Understanding the mechanisms of osteolysis at a molecular level will generate more effective therapeutic agents for patients with this devastating complication of cancer. (C) 2000 American Cancer Society.