Holen, I. orcid.org/0000-0002-8759-6913, Walker, M., Nutter, F. et al. (4 more authors) (2016) Oestrogen receptor positive breast cancer metastasis to bone: inhibition by targeting the bone microenvironment in vivo. Clinical & Experimental Metastasis, 33 (3). pp. 211-224. ISSN 0262-0898
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2015. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
Keywords: | ER plus ve; Breast cancer; Bone metastasis; Zoledronic acid; Estradiol |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > The Medical School (Sheffield) > Division of Genomic Medicine (Sheffield) > Department of Oncology and Metabolism (Sheffield) The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number YORKSHIRE CANCER RESEARCH SPP022 BREAST CANCER CAMPAIGN 2008MayPHD01 NATIONAL CENTRE FOR THE REPLACEMENT, REFINEMENT AND REDUCTION OF ANIMALS IN RESEARCH UNSPECIFIED YORKSHIRE CANCER RESEARCH S383 CRTF EXELEXIS NONE EUROPEAN COMMISSION - FP6/FP7 BONE-NET - 264817 SHEFFIELD HOSPITALS CHARITABLE TRUST AJT/JS/3170(2)/111220 BREAST CANCER CAMPAIGN 2013NovPR173 WESTON PARK HOSPITAL CANCER CHARITY CA126 WESTON PARK HOSPITAL CANCER CHARITY SG108 BREAST CANCER CAMPAIGN 2011 May SP03 WESTON PARK HOSPITAL CANCER CHARITY CA114 BREAST CANCER CAMPAIGN 3010NOVPhD17 WESTON PARK HOSPITAL CANCER CHARITY CA113 GALAPAGOS SASU None GALAPAGOS SASU None BREAST CANCER CAMPAIGN 2008NovSP21 WESTON PARK HOSPITAL CANCER APPEAL SG85 WESTON PARK HOSPITAL CANCER APPEAL CA105 NOVARTIS PHARMA CORP NONE WESTON PARK HOSPITAL CANCER APPEAL CA100 SHEFFIELD HOSPITALS CHARITABLE TRUST (SPECIAL TRUSTEES) AJT/JS/3170/050604/5 WESTON PARK HOSPITAL CANCER APPEAL CA91 BREAST CANCER CAMPAIGN 2007MayPR05 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST CA76 BREAST CANCER CAMPAIGN 2003:497 BREAST CANCER CAMPAIGN 2002:288 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST UNSPECIFIED SHEFFIELD HOSPITALS CHARITABLE TRUST (SPECIAL TRUSTEES) PRW/JS/2315 SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST UNSPECIFIED DEPARTMENT OF TRADE AND INDUSTRY UNSPECIFIED SHEFFIELD TEACHING HOSPITALS NHS FOUNDATION TRUST UNSPECIFIED YORKSHIRE CANCER RESEARCH NONE EUROPEAN COMMISSION - FP6/FP7 LSHC-CT-2006-018858 WELLCOME TRUST (THE) 070779/Z/03/Z WESTON PARK HOSPITAL CANCER APPEAL CA78 YORKSHIRE CANCER RESEARCH S281 WELLCOME TRUST (THE) 060361 EUROPEAN COMMISSION - FP6/FP7 MEST-CT-2005-020970 WELLCOME TRUST (THE) VS/05/SHE/A4 RCUK (WAKEHAM ADJUSTMENT) NONE RCUK (WAKEHAM ADJUSTMENT) NONE RCUK (WAKEHAM ADJUSTMENT) NONE RCUK (WAKEHAM ADJUSTMENT) NONE BREAST CANCER CAMPAIGN 2012NovSP033 MEDICAL RESEARCH COUNCIL MR/K015052/1 ARTHRITIS RESEARCH CAMPAIGN UNSPECIFIED YORKSHIRE CANCER RESEARCH EK/RC INTERNATIONAL BONE AND MINERAL SOCIETY None WESTON PARK HOSPITAL CANCER CHARITY CA142 BREAST CANCER CAMPAIGN UNSPECIFIED ROCHE DIAGNOSTICS NONE CANCER RESEARCH UK (CRUK) C43420/A14234 YORKSHIRE CANCER RESEARCH SHEFFIELD ENDOWNMENT RELEASE SHEFFIELD HOSPITALS CHARITABLE TRUST 111218 CANCER RESEARCH UK (CRUK) C43420/A14233 CANCER RESEARCH UK (CRUK) C43420/A14238 WESTON PARK HOSPITAL CANCER CHARITY CA128 CANCER RESEARCH UK (CRUK) C43420/A14233 CANCER RESEARCH UK (CRUK) C43420/A17904 CANCER RESEARCH UK (CRUK) UNSPECIFIED CANCER RESEARCH UK (CRUK) C43420/A14236 CANCER RESEARCH UK (CRUK) C43420/A14233 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 03 Aug 2016 13:39 |
Last Modified: | 03 Aug 2016 13:39 |
Published Version: | http://www.doi.org/10.1007/s10585-015-9770-x |
Status: | Published |
Publisher: | Springer Verlag |
Refereed: | Yes |
Identification Number: | 10.1007/s10585-015-9770-x |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:92217 |