Zoledronic Acid Has Differential Antitumor Activity in the Pre- and Postmenopausal Bone Microenvironment In Vivo

Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast...

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Bibliographic Details
Published in:	Clinical cancer research Vol. 20; no. 11; pp. 2922 - 2932
Main Authors:	OTTEWELL, Penelope D, NING WANG, BROWN, Hannah K, REEVES, Kimberly J, FOWLES, C. Anne, CROUCHED, Peter I, EATON, Colby L, HOLEN, Ingunn
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-06-2014
Subjects:	Animals Antineoplastic agents Biological and medical sciences Bone and Bones - drug effects Bone Density Conservation Agents - pharmacology Bone Neoplasms - secondary Breast Neoplasms - pathology Cell Line, Tumor Cellular Microenvironment Diphosphonates - pharmacology Disease Models, Animal Female Humans Imidazoles - pharmacology Medical sciences Mice Mice, Inbred BALB C Mice, Nude Microscopy, Confocal Osteoclasts - drug effects Osteoclasts - metabolism Ovariectomy Pharmacology. Drug treatments Postmenopause - drug effects Postmenopause - metabolism Premenopause - drug effects Premenopause - metabolism Real-Time Polymerase Chain Reaction X-Ray Microtomography Xenograft Model Antitumor Assays Zoledronic Acid Antineoplastic agent Antiosteoporotic Menopause Antiresorptive agent Diphosphonic acid derivatives Microenvironment Bisphosphonates Biological activity Osteoarticular system In vivo Zoledronic acid Postmenopause Bone
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Summary:	Clinical trials in early breast cancer have suggested that benefits of adjuvant bone-targeted treatments are restricted to women with established menopause. We developed models that mimic pre- and postmenopausal status to investigate effects of altered bone turnover on growth of disseminated breast tumor cells. Here, we report a differential antitumor effect of zoledronic acid (ZOL) in these two settings. Twleve-week-old female Balb/c-nude mice with disseminated MDA-MB-231 breast tumor cells in bone underwent sham operation or ovariectomy (OVX), mimicking the pre- and postmenopausal bone microenvironment, respectively. To determine the effects of bone-targeted therapy, sham/OVX animals received saline or 100 μg/kg ZOL weekly. Tumor growth was assessed by in vivo imaging and effects on bone by real-time PCR, micro-CT, histomorphometry, and measurements of bone markers. Disseminated tumor cells were detected by two-photon microscopy. OVX increased bone resorption and induced growth of disseminated tumor cells in bone. Tumors were detected in 83% of animals following OVX (postmenopausal model) compared with 17% following sham operation (premenopausal model). OVX had no effect on tumors outside of bone. OVX-induced tumor growth was completely prevented by ZOL, despite the presence of disseminated tumor cells. ZOL did not affect tumor growth in bone in the sham-operated animals. ZOL increased bone volume in both groups. This is the first demonstration that tumor growth is driven by osteoclast-mediated mechanisms in models that mimic post- but not premenopausal bone, providing a biologic rationale for the differential antitumor effects of ZOL reported in these settings. Clin Cancer Res; 20(11); 2922-32. ©2014 AACR.
ISSN:	1078-0432 1557-3265
DOI:	10.1158/1078-0432.CCR-13-1246