The differential anti-tumour effects of zoledronic acid in breast cancer -evidence for a role of the activin signaling pathway

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• 作者：Caroline Wilson ; Penelope Ottewell ; Robert E Coleman ; Ingunn Holen
• 关键词：Breast cancer ; Zoledronic acid ; Activin ; Follistatin ; Phosphorylated Smad2
• 刊名：BMC Cancer
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：15
• 期：1
• 全文大小：1,941 KB
• 参考文献：1. Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane M, et al. The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer. Br J Cancer. 2010;102(7):1099-05. doi:10.1038/sj.bjc.6605604. CrossRef
  2. Aft RL, Naughton M, Trinkaus K, Weilbaecher K. Effect of (Neo)adjuvant zoledronic acid on disease-free and overall survival in clinical stage II/III breast cancer. Br J Cancer. 2012;107(1):7-1. doi:10.1038/bjc.2012.210. CrossRef
  3. Horiguchi JHY, Miura D. A randomized controlled trial comparing zoledronic acid plus chemotherapy with chemotherapy alone as a neoadjuvant treatment in patients with HER2-negative primary breast cancer. J Clin Oncol. 2013;31:2013. suppl; abstr 1029.
  4. Rachner TD, Singh SK, Schoppet M, Benad P, Bornhauser M, Ellenrieder V, et al. Zoledronic acid induces apoptosis and changes the TRAIL/OPG ratio in breast cancer cells. Cancer Lett. 2010;287(1):109-6. doi:10.1016/j.canlet.2009.06.003. CrossRef
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  6. Winter MC, Wilson C, Syddall SP, Cross S, Evans A, Ingram C, et al. Neoadjuvant chemotherapy with or without zoledronic acid in early breast cancer–a randomized biomarker pilot study. Clin Cancer Res. 2013;19(10):2755-5. doi:10.1158/1078-0432.CCR-12-3235. CrossRef
  7. Wilson CWM, Coleman RE, Ottewell P, Evans AC, Holen I. Differential anti-tumour effects of zoledronic acid in breast cancer according to ER status and levels of female hormones. Miami, Florida: Cancer and Bone Society and the International Bone and Mineral Society; 2013.
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  11. Kalkhoven E, Roelen BA, de Winter JP, Mummery CL, Van den Eijnden-Van Raaij AJ, Van der Saag PT, et al. Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines. Cell Growth Differ. 1995;6(9):1151-1.
  12. Razanajaona D, Joguet S, Ay AS, Treilleux I, Goddard-Leon S, Bartholin L, et al. Silencing of FLRG, an antagonist of activin, inhibits human breast tumor cell growth. Cancer Res. 2007;67(15):7223-. doi:10.1158/0008-5472.CAN-07-0805. CrossRef
  13. Ottewell PD, Monkkonen H, Jones M, Lefley DV, Coleman RE, Holen I. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst. 2008;100(16):1167-8. doi:10.1093/jnci/djn240. CrossRef
  14. Burdette JE, Jeruss JS, Kurley SJ, Lee EJ, Woodruff TK. Activin A mediates growth inhibition and cell cycle arrest through Smads in human breast cancer cells. Cancer Res. 2005;65(17):7968-5. doi:10.1158/0008-5472.CAN-04-3553.
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  16. Reis FM, Luisi S, Carneiro MM, Cobellis L, Frederico M, Camargos AF, e
• 作者单位：Caroline Wilson (1)
  Penelope Ottewell (2)
  Robert E Coleman (1)
  Ingunn Holen (1)
  
  1. Academic Unit of Clinical Oncology, University of Sheffield, Medical School, Sheffield, UK
  2. Academic Department of Oncology, University of Sheffield, Medical School, Sheffield, UK
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

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.