Abstract
BackgroundNeo-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.MethodsThe 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.ResultsActivin 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.ConclusionsThis 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.
Highlights
Neo-adjuvant breast cancer clinical trials of zoledronic acid (ZOL) have shown that patients with oestrogen negative (ER-ve) tumours have improved disease outcomes
Activin A inhibits the proliferation of ER + ve and ER-ve breast cancer cells Previous reports have shown that proliferation of ER + ve cells is inhibited by activin [14], but the effect of activin on proliferation of ER-ve cell lines is less clear [11]
Both the ER-ve (MDA-MB-231) and ER + ve (MCF7) cells showed a significant decrease in proliferation compared to control following addition of activin A on days 1 and 3 (Figure 2A + B) which was lost by day 5
Summary
Neo-adjuvant breast cancer clinical trials of zoledronic acid (ZOL) have shown that patients with oestrogen negative (ER-ve) tumours have improved disease outcomes. The addition of ZOL to chemotherapy reduced serum follistatin levels at day 5 post treatment in patients with ER-ve tumours compared to patients receiving chemotherapy alone [7]. This may reflect a fall in the Wilson et al BMC Cancer (2015) 15:55 secretion of follistatin from ER-ve breast tumours that is not seen in ER + ve tumours
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