Triptonide Inhibits The Growth And Metastasis Of Triple Negative Breast Cancer(TNBC) And Its Mechanism

Triple negative breast cancer(TNBC)is the worst prognosis in breast cancer,with a 5-year survival rate of less than 15%.Because TNBC is more aggressive and metastatic than other types of breast cancer,patients have a high recurrence rate within three years of treatment.Once tumor metastasis occurs,the patient's median survival time is shortened to less than 6 months.For a long time,the lack of effective anti-triple breast cancer drugs at home and abroad has become the bottleneck of tresament of triple negative breast cancer metastasis.Therefore,how to discover effective therapeutics against anti-triple negative breast cancer metastasis has become an urgent scientific problem to be solved.The main reason for the poor prognosis of triple negative breast cancer is that this type of breast cancer cells is highly metastatic,and tumor metastasis can cause the failure of important organs and lead to the death of patients.Metastasis of triple-negative breast cancer is related to the abnormal activation of epithelial-mesenchymal transition(EMT),causing cells to detach from the primary tumor site and settle to distant organs,which is an important reason for the high metastatic ability of triple-negative breast cancer cells.A large number of studies have proved that the transcription factor Twistl is a key gene for inducing cell EMT and is necessary for tumor metastasis.The overexpression of Twist1 in triple negative breast cancer promotes the occurrence and development of human breast cancer,and high expression level of Twist1 is positively correlated with tumor resistance.Clinically,there is no effective drug targeting Twist1.Therefore,how to effectively suppress Twistl is a scientific question to be solved in the research of cancer metastasis.We can't help but imagine whether we can uncover new active compounds against triple negative breast cancer from the treasure house of the traditional Chinese medicinal herbs.Using this as a research strategy,an active anti-cancer monomer triptonide was screened and identified from the traditional Chinese medicinal herbs.However,whether triptonide can inhibit the growth and metastasis of triple negative breast cancer has not been reported in the literature at home and abroad.We raise a scientific question:Can triptonide inhibit the growth and metastasis of triple negative breast cancer?To answer the question,we designed the strategy and experiments to study the effect of triptonide on triple negative breast cancer at the three levels:triple negative breast cancer cell level,orthotopic tumor transplantation in mice,and molecular mechanism.In the current study,we found that triptonide strongly inhibits the tumorigenicity of triple negative breast cancer.At the cellular level,triptonide at a very low concentration of 15 nM can significantly inhibit the cell proliferation of triple-negative breast cancer cells,and the IC50(half of the inhibitory concentration)of BT-549 cells is 12.089 nM,the IC50 values of MDA-MB-231 and MDA-MB-468 were 15.597 nM and 14.428 nM,respectively;after 10 nM triptonide treatment,the number of clones formation of the two cancer cells was reduced by 5 times;in tumor-bearing mice,the tumor growth inhibition rate of triptonide is as high as 95%,and the toxicity and side effects are low.In addition,triptonide can also inhibit the metastasis of triple negative breast cancer cells.At the cellular level,the effect of triptonide at a concentration of 10 nM can reduce the cell migration and invasion ability of triple negative breast cancer by more than 3 times;in tumor-bearing mice,triptonide can inhibit the triple negative breast cancer cells spread to the near distance of ribs and the long distance of lung.Molecular mechanistic research reveals that triptonide can accelerate the lysosomal degradation of Twistl protein and reduce the protein amount of the protein in triple negative breast cancer cells;Furthermore,triptonide can reduce the protein of Notchl and its downstream p-NF-?B expression,reuslting in a robust inhibiton of the growth and metastasis of triple negative breast cancer.In summary,we found that triptonide can effectively inhibit the tumorigenicity and metastasis of triple negative breast cancer cells,ande revealed the molecular mechanism of triptonide-mediated inhibition of the growth and metastasis of triple-negative breast cancer.Our findings provide a new strategy to target Twistl,Notch1,and NF-?B signaling pathway for triple negative breast cancer therapy,and offer a new drug candidate for treatment of triple-negative breast cancer.