Research On GPR Activation Inducing Chemoresistance In Breast Cancer

Development of chemoresistance is a persistent problem during the treatment of breast cancer.The identification of the molecular mechanisms underlying chemoresistance is mandatory to achieve advancement in breast cancer therapy.We found that the expression of GPR120 is upregulated in adriamycin resistant cell line,MCF-7/ADM,when compared with adriamycin sensitive cell line,MCF-7/WT.Activating GPR120 with it's agonist GW9508 could enhance the level of resistance to adriamycin in MCF-7/WT,which was manifested by half maximal inhibitory concentration,IC50.This means GPR120 is a chemoresistant molecule,and further studies showed that GPR120 activation could increase the expression of ABC transporters,including ABCC1,ABCC2,ABCG2.GPR120 is a GPCR activated by long fatty acids.In breast cancer patients,the total level of fatty acids in the tumor microenvironment is higher when compared with the adjacent by Gas Chromatography-Mass Spectrometer.Some fatty acids have been reported as ligands which could activate GPR120,and the level of these fatty acids is also higher.Maybe,elevated level of fatty acids in the tumor microenvironment is associated with GPR120 activation itself.Because our data showed that GPR120 activation could increase the level of fatty acids in cell culture supernatant through regulating fatty acid synthetase and other molecules related to fatty acid synthesis.This autocrine loop promotes the development of chemoresistance in breast cancer.Analysis of human breast cancer tissues revealed that high expression of GPR120 suggested poor sensitivity to chemotherapy.Our data provide the first evidence that the correlations of GPR120 expression and chemotherapy sensitivity,and thus the level of GPR120 expression could predict curative effects of chemotherapy.These results suggest that blockade of GPR120 may overcome chemoresistance and improve the outcome of breast cancer patients.