NNMT Promotes Metastasis Of Triple-Negative Breast Cancer Through Promoting EMT

Background Of all breast cancer subtypes,triple-negative breast cancer(TNBC)which lacks effective targeted therapy has the highest metastasis rates and the poorest overall survival rates.Therefore,the TNBC treatment urgently needs to be improved.The majority of deaths associated with cancer are due to the metastasis of the original tumor cells to sites distant from the initial or primary tumor.Nicotinamide-N-Methyltransferase(NNMT)is known to be a methylase which abundantly expressed in many types of cancer and linked to cancer cell initiation,progression,and metastasis.Recent study of our group has reported high expression of NNMT in breast cancer.NNMT promoted the cell proliferation through inhibiting cell apoptosis and accelerating cell cycle progression.However,the role of NNMT in triple-negative breast cancer metastasis has not been reported,so the role and mechanism of NNMT in triple-negative breast cancer metastasis deserve to be further studied,which may provide a novel strategy to treat TNBC by targeting metastasis.Objective To explore whether NNMT affects the metastasis of triple-negative breast cancer cells and its possible mechanism,and to provide theoretical basis for clinical targeted treatment of triple-negative breast cancer by NNMT.Methods 1.Through the open breast cancer database,the expression of NNMT in triple-negative breast cancer,the relationship between NNMT and prognosis,metastasis and metastasis related molecules were analyzed.2.The tissue samples of triple-negative and non-triple-negative breast cancer were collected,and the expression of NNMT was detected by immunohistochemistry to verify the high expression of NNMT in triple-negative breast cancer.3.The expression of NNMT in various triple-negative breast cancer cell lines was detected and cell models with different expression levels of NNMT in triple-negative breast cancer cells were constructed.4.Cell migration and invasion were detected by wound healing assay,Transwell and Matrigel experiment using the cell models mentioned above.5.Cell metastasis in SCID mice was detected by establishing SCID mice lung metastasis models using the cell models mentioned above.6.Western blot was used to detect the expression of EMT molecules in cells using the cell models mentioned above,and the effect of NNMT on the expression of EMT molecules was analyzed,so as to explore the mechanism of NNMT promoting the metastasis and invasion of triple-negative breast cancer cells.Results 1.We found that NNMT was highly expressed in triple-negative breast cancer,and was correlated with poor prognosis and high distant metastasis,and positively correlated with the expression of EMT-related molecular markers N-cadherin and Vimentin through analyzing databases.2.We found that NNMT was highly expressed in triple-negative breast cancer tissues collected from clinical breast cancer patients.3.We found that NNMT is highly expressed in triple-negative breast cancer cell lines through analyzing the data extracted from the literature.We tested various triple-negative breast cancer cell lines to verify the high expression of NNMT,and successfully constructed triple-negative breast cancer cell models with different levels of NNMT.4.NNMT promoted the migration and invasion of triple-negative breast cancer cells in vivo.5.NNMT promoted the metastasis of triple-negative breast cancer cells in vitro.6.NNMT promotes the EMT in triple-negative breast cancer cells,which is speculated to be the mechanism of NNMT to promote the metastasis and invasion of triple-negative breast cancer cells.Conclusions Our study found that NNMT was highly expressed in triple-negative breast cancer and was positively associated with poor prognosis and increased metastasis of triple-negative breast cancer.Our study confirmed that NNMT promoted the metastasis of triple-negative breast cancer cells by promoting EMT.