Cellular mechanisms of bone resorption in breast carcinoma

The cellular mechanisms that account for the increase in osteoclast numbers and bone resorption in skeletal breast cancer metastasis are unclear. Oste oclasts are marrow-derived cells which form by fusion of mononuclear phagoc yte precursors that circulate in the monocyte fraction. In this study we ha ve determined whether circulating osteoclast precursors are increased in nu mber or have an increased sensitivity to humoral factors for osteoclastogen esis in breast cancer patients with skeletal metastases (rt hypercalcaemia) compared to patients with primary breast cancer and age-matched normal con trols. Monocytes were isolated and cocultured with UMR 106 osteoblastic cel ls in the presence of 1.25 dihydroxyvitamin D-3 [1,25(OH)(2)D-3] and human macrophage colony stimulating factor (M-CSF) on coverslips and dentine slic es. Limiting dilution experiments showed that there was no increase in the number of circulating osteoclast precursors in breast cancer patients with skeletal metastases (+/- hypercalcaemia) compared to controls. Osteoclast p recursors in these patients also did not exhibit increased sensitivity to 1 .25(OH)(2)D-3 or M-CSF in terms of osteoclast formation. The addition of pa rathyroid hormone-related protein and interleukin-6 did not increase osteoc last formation. The addition of the supernatant of cultured breast cancer c ell lines (MCF-7 and MDA-MB-435), however, significantly increased monocyte -osteoclast formation in a dose-dependent fashion. These results indicate t hat the increase in osteoclast formation in breast cancer is not due to an increase in the number/nature of circulating osteaclast precursors. They al so suggest that tumour cells promote osteoclast formation in the bone micro environment by secreting soluble osteoclastogenic factor(s). (C) 2001 Cance r Research Campaign http://www.bjcancer.com.