Wilson, C., Ottewell, P., Coleman, R.E. et al. (1 more author) (2015) The differential anti-tumour effects of zoledronic acid in breast cancer - evidence for a role of the activin signaling pathway. BMC Cancer, 15. 55. ISSN 1471-2407
Abstract
Background Neo-adjuvant breast cancer clinical trials of zoledronic acid (ZOL) have shown that patients with oestrogen negative (ER-ve) tumours have improved disease outcomes. We investigated the molecular mechanism behind this differential anti-tumour effect according to ER status, hypothesising it may in part be mediated via the activin signaling pathway.
Methods The effects of activin A, its inhibitor follistatin and zoledronic acid on proliferation of breast cancer cells was evaluated using either an MTS proliferation assay or trypan blue. Secretion of activin A and follistatin in conditioned medium (CM) from MDA-MB-231, MDA-MB-436, MCF7 and T47D cell lines were measured using specific ELISAs. The effects of ZOL on phosphorylation domains of Smad2 (pSmad2c + pSmad2L) were evaluated using immunofluorescence. Changes seen in vitro were confirmed in a ZOL treated subcutaneous ER-ve MDA-MB-436 xenograft model.
Results Activin A inhibits proliferation of both ER-ve and oestrogen positive (ER + ve) breast cancer cells, an effect impaired by follistatin. ZOL significantly inhibits proliferation and the secretion of follistatin from ER-ve cells only, which increases the biological activity of the canonical activin A pathway by significantly increasing intracellular pSmad2c and decreasing nuclear accumulation of pSmad2L. In vivo, ZOL significantly decreases follistatin and pSmad2L expression in ER-ve subcutaneous xenografts compared to saline treated control animals.
Conclusions This is the first report showing a differential effect of ZOL, according to ER status, on the activin pathway and its inhibitors in vitro and in vivo. These data suggest a potential molecular mechanism contributing to the differential anti-tumour effects reported from clinical trials and requires further evaluation in clinical samples.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2015 Wilson et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
Keywords: | Breast cancer; Zoledronic acid; Activin; Follistatin; Phosphorylated Smad2 |
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 Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 10 Jun 2015 11:29 |
Last Modified: | 03 Nov 2016 01:56 |
Published Version: | http://dx.doi.org/10.1186/s12885-015-1066-7 |
Status: | Published |
Publisher: | BioMed Central |
Refereed: | Yes |
Identification Number: | 10.1186/s12885-015-1066-7 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:85750 |