title: Bone resorption increases tumour growth in a mouse model of osteosclerotic breast cancer metastasis.
abstract: Osteosclerotic metastases account for 20% of breast cancer metastases with the remainder osteolytic or mixed. In mouse models, osteolytic metastases are dependent on bone resorption for their growth. However, whether the growth of osteosclerotic bone metastases depends on osteoclast or osteoblast actions is uncertain. In this study, we investigate the effects of high and low bone resorption on tumour growth in a mouse model of osteosclerotic metastasis. We implanted human breast cancer, MCF-7, cells into the tibiae of mice. Low and high levels of bone resorption were induced by osteoprotegerin (OPG) treatment or calcium deficient diet respectively. We demonstrate that OPG treatment significantly reduces tumour area compared to vehicle (0.42 +/- 0.06 vs. 1.27 +/- 0.16 mm2, P < 0.01) in association with complete inhibition of osteoclast differentiation. In contrast, low calcium diet increases tumour area compared to normal diet (0.90 +/- 0.30 vs. 0.58 +/- 0.20 mm2, P < 0.05) in association with increased osteoclast numbers (84.44 +/- 5.18 vs. 71.11 +/- 3.56 per mm2 bone lesion area, P < 0.05). Osteoblast surfaces and new woven bone formation were similarly increased within the tumour boundaries in all treatment groups. Tumour growth in this model of osteosclerotic metastasis is dependent on ongoing bone resorption, as has been observed in osteolytic models. Bone resorption, rather than bone formation, apparently mediates this effect as osteoblast surfaces in the tumour mass were unchanged by treatments. Treatment of breast cancer patients through correction of calcium deficiency and/or with anti-resorptive agents such as OPG, may improve patient outcomes in the adjuvant as well as palliative settings.
authors.affiliation: Bone Research Program, ANZAC Research Institute, University of Sydney, Hospital Road, Concord, Sydney, Australia.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zheng
authors.forename: Hong
authors.initials: H
authors.lastname: Zhou
authors.forename: Colette
authors.initials: C
authors.lastname: Fong-Yee
authors.forename: James R K
authors.initials: JR
authors.lastname: Modzelewski
authors.forename: Markus J
authors.initials: MJ
authors.lastname: Seibel
authors.forename: Colin R
authors.initials: CR
authors.lastname: Dunstan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000556:secondary*; D001862:Bone Resorption / Q000188:drug therapy / Q000503:physiopathology*; D002118:Calcium / Q000008:administration & dosage; D002454:Cell Differentiation / Q000187:drug effects; D004032:Diet; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000150:complications / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D053244:Osteoprotegerin / Q000494:pharmacology; D010026:Osteosclerosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*
chemical_list: D053244:Osteoprotegerin; D002118:Calcium