title: Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo.
abstract: Clinical trials have shown that adjuvant Zoledronic acid (ZOL) reduces the development of bone metastases irrespective of ER status. However, post-menopausal patients show anti-tumour benefit with ZOL whereas pre-menopausal patients do not. Here we have developed in vivo models of spontaneous ER+ve breast cancer metastasis to bone and investigated the effects of ZOL and oestrogen on tumour cell dissemination and growth. ER+ve (MCF7, T47D) or ER-ve (MDA-MB-231) cells were administered by inter-mammary or inter-cardiac injection into female nude mice ± estradiol. Mice were administered saline or 100 μg/kg ZOL weekly. Tumour growth, dissemination of tumour cells in blood, bone and bone turnover were monitored by luciferase imaging, histology, flow cytometry, two-photon microscopy, micro-CT and TRAP/P1NP ELISA. Estradiol induced metastasis of ER+ve cells to bone in 80-100 % of animals whereas bone metastases from ER-ve cells were unaffected. Administration of ZOL had no effect on tumour growth in the fat pad but significantly inhibited dissemination of ER+ve tumour cells to bone and frequency of bone metastasis. Estradiol and ZOL increased bone volume via different mechanisms: Estradiol increased activity of bone forming osteoblasts whereas administration of ZOL to estradiol supplemented mice decreased osteoclast activity and returned osteoblast activity to levels comparable to that of saline treated mice. ER-ve cells require increased osteoclast activity to grow in bone whereas ER+ve cells do not. Zol does not affect ER+ve tumour growth in soft tissue, however, inhibition of bone turnover by ZOL reduced dissemination and growth of ER+ve breast cancer cells in bone.
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
authors.forename: I
authors.initials: I
authors.lastname: Holen
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
authors.forename: F
authors.initials: F
authors.lastname: Nutter
authors.affiliation: Bone Biology, Department of Human Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield, S10 2RX, UK.
authors.forename: A
authors.initials: A
authors.lastname: Fowles
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK.
authors.forename: C A
authors.initials: CA
authors.lastname: Evans
authors.affiliation: Bone Biology, Department of Human Metabolism, Mellanby Centre for Bone Research, University of Sheffield, Sheffield, S10 2RX, UK.
authors.forename: C L
authors.initials: CL
authors.lastname: Eaton
authors.affiliation: Academic Unit of Clinical Oncology, Department of Oncology, Medical School, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, UK. p.d.ottewell@sheffield.ac.uk.
authors.forename: P D
authors.initials: PD
authors.lastname: Ottewell
mesh_terms: D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000556:secondary*; D016723:Bone Remodeling / Q000187:drug effects*; D001943:Breast Neoplasms / Q000556:secondary*; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D004958:Estradiol / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D011960:Receptors, Estrogen / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*; D055114:X-Ray Microtomography; D023041:Xenograft Model Antitumor Assays; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D011960:Receptors, Estrogen; D004958:Estradiol; D000077211:Zoledronic Acid
keywords: Bone metastasis; Breast cancer; ER+ve; Estradiol; Zoledronic acid