Targeting BMP-1 enhances anti-tumoral effects of doxorubicin in metastatic mammary cancer: common and distinct features of TGF-β inhibition

PurposeMammary carcinoma is comprised heterogeneous groups of cells with different metastatic potential. 4T1 mammary carcinoma cells metastasized to heart (4THM), liver (4TLM) and brain (4TBM) and demonstrate cancer-stem cell phenotype. Using these cancer cells we found thatTGF-beta is the top upstream regulator of metastatic process. In addition, secretion of bone morphogenetic protein 1 (BMP-1), which is crucial for the proteolytic release of TGF-beta, was markedly high in metastatic mammary cancer cells compared to non-metastatic cells. Although TGF-beta inhibitors are in clinical trials, systemic inhibition of TGF-beta may produce heavy side effects. We here hypothesize that inhibition of BMP-1 proteolytic activity inhibits TGF-beta activity and induces anti-tumoral effects.Method and ResultsEffects of specific BMP-1 inhibitor on liver and brain metastatic murine mammary cancer cells (4TLM and 4TBM), as well as on human mammary cancer MDA-MB-231 and MCF-7 cells, were examined and compared with the results of TGF-beta inhibition. Inhibition of BMP-1 activity markedly suppressed proliferation of cancer cells and enhanced anti-tumoral effects of doxorubicin. Inhibition of BMP-1 activity but not of TGF-beta activity decreased colony and spheroid formation. Differential effects of BMP-1 and TGF-beta inhibitors on TGF-beta secretion was also observed.ConclusionsThese results demonstrated for the first time that the inhibition of BMP-1 activity has therapeutic potential for treatment of metastatic mammary cancer and enhances the anti-tumoral effects of doxorubicin.