Mechanism Of The Effect Of Cyanobacterial Secondary Metabolite Zearalenone On Hedgehog Pathway In Breast Cancer Cells

The ecological problems by the outburst of cyanobacteria are becoming increasingly severe,and the estrogen-like zearalenone(ZEA,secondary metabolite of cyanobacteria)has teratogenic effects on aquatic animal embryos.The Hedgehog signaling pathway is generally activated during embryonic development stage,as well as many cancers including breast cancer.The frequency of estrogen receptor(ER)-positive breast cancers increases dramatically with estrogen-like exposure.However,the link between estrogenlike estrogen and Hedgehog pathway in ER-positive breast cancer cells remains unclear.Therefore,this research aim to address this scientific question using various types of breast cancer cells.Firstly,ZEA was used to treat the following cells in this experiment: normal breast cell 184B5,ER-negative breast cancer cells HCC-1937,MDA-MB-231,ER-positive breast cancer cells T47 D,MCF-7.It was found that different concentrations of ZEA had different effects on the proliferation and Hedgehog pathway protein expression in these cells.In normal breast cells,low concentration did not affect cell proliferation and Hedgehog pathway protein expression,while high concentration inhibited proliferation and pathway protein expression.In ER-negative breast cancer cells,low concentration of ZEA showed no effect on cell proliferation and Hedgehog pathway protein expression,while high concentration inhibited proliferation but did not affect protein expression.ERpositive breast cancer cells promote cell proliferation and Hedgehog pathway protein expression at low concentrations,and inhibit proliferation and protein expression at high concentrations.The results indicated that ER-positive breast cancer cells were more sensitive to ZEA treatment compared to normal breast cells and ER-negative cells,which associated ZEA effects with Hedgehog pathwaysWe further validate the involvement in ZEA effects of Hedgehog pathway,by combination Hedgehog pathway inhibitors or agonists with ZEA,our results demonstrated that low concentrations of ZEA promoted the expression of Hedgehog pathway proteins,and high concentrations of ZEA inhibited the expression of Hedgehog pathway proteins.Finally,we tested the effect of ZEA on the stemness and epithelial-mesenchymal transition(EMT)process of ER-positive breast cancer cells controlled by the Hedgehog pathway,and found the consistent biphasic dose-response,that low concentration promotes breast cancer cell stemness and EMT process;high concentration inhibits breast cancer cell stemness and EMT process.In summary,we found that ER-positive breast cancer cells are more sensitive and biphasic response to ZEA.ZEA mediates the stemness and EMT process of breast cancer cells by regulating the Hedgehog pathway in ER-positive breast cancer cells,thereby affecting the occurrence and development of ER-positive breast cancer.low concentrations of ZEA activate the Hedgehog pathway and promote the stemness and EMT process of breast cancer cells,while high concentrations of ZEA show the opposite regulatory mechanism and biological effects.These findings provide some new ideas for the prevention and clinical treatment of ER-positive breast cancer.Meanwhile,it affords a certain explanation for the ecological problems of cyanobacteria from the perspective of molecular.