| ObjectiveBreast cancer with an increasing incidence is a hormone-dependent malignant tumor.Surgical treatment is its primary treatment,while endocrine therapy is another important treatment to prevent recurrence and metastasis of breast cancer patients.However,the abnormal blood lipid events caused by endocrine therapy have become a prominent problem affecting the quality of life of breast cancer patients,and its prevention and treatment has become an urgent problem to be solved.As people pay more and more attention to traditional Chinese medicine(TCM),the clinical treatment and basic research of TCM in cancer have been paid more and more attention.It has been found that TCM can not only regulate immune microenvironment,promote tumor dormancy or apoptosis,but also combine with western medicine to achieve synergy and attenuation,so as to improve the quality of life of patients and prolong the survival time of patients.The method of soothing 1iver and invigorating spleen is the main treatment of endocrine-related dyslipidemia in breast cancer,which has unique advantages.Previous studies have suggested that liver estrogen receptor a(ER a)is a target organ which depends on the physiological effect of estrogen,and liver low density lipoprotein receptor(LDLR)is also a key receptor for regulating blood lipids.When LDLR decreases,abnormal lipid metabolism can lead to abnormal lipid levels.I speculate that the effect of hormone level on blood lipid may be due to the decrease of ER alpha receptor in vivo,which leads to the decrease of LDLR in liver.The method of soothing liver and invigorating spleen also changes the micro-environment in vivo through ER a-LDLR,so as to improve the related dyslipidemia caused by endocrine therapy of breast cancer.On the one hand,through retrospective study of clinical cases,this study analyzed the correlation of endocrine therapy,dyslipidemia and Liver-soothing and spleen-invigorating therapy for breast cancer;on the other hand,through in vivo experiments,the intervention effect of Liver-soothing and spleen-invigorating therapy on dyslipidemia after endocrine therapy for breast cancer and the regulatory mechanism of ERa-LDLR mediated pathway in endocrine therapy related dyslipidemia.Finally,the regulating effect of Liver-soothing and spleen-invigorating therapy on ER a-LDLR mediated pathway in endocrine therapy-related dyslipidemia is clarified,whieh provides a theoretical basis for its clinical application and further research on the treatment of endocrine therapy related dyslipidemia with Chinese herbal compound.MethodsThis study is divided into two parts.The first part is to collect the cases of breast cancer patients undergoing or completed endocrine therapy from September 2016 to September 2018 in the outpatient and inpatient departments of the Department of traditional Chinese medicine and mammary gland of Guangdong People' s Hospital.They are divided into two groups:eontrol group(no intervention of other lipid drugs after endocrine therapy),and Liver-soothing and Spleen-strengthening group(Shugan Jianpi powder after endocrine therapy).The basic situation,endocrine treatment program,blood lipid status,intervention methods(no intervention,Liver-soothing and spleen-invigorating therapy)and outcomes of each group were summarized and analyzed.The correlation between endocrine therapy and dyslipidemia,Liver-soothing and spleen-invigorating therapy in breast cancer patients was summarized and analyzed.The second part:In vivo experiments were used to establish the model of dyslipidemia related to endocrine therapy in C57BL/6 mice.The model mice were divided into six groups:normal control group(without endocrine therapy),model group,atorvastatin group,low,medium and high dose group of Shugan-Jianpi powder.The general situation and Serum estrogen and progesterone levels of mice in each group were observed.The levels of serum estrogen and progesterone,four blood lipids,the expression of ER a,PR and LDLR in liver were detected by PCR,Western blot and inununohistochemistry.Results1.The correlation of endocrine therapy,dyslipidemia and Liver-soothing and spleen-invigorating therapy in patients with breast cancer(1)The 56 cases included in the study were divided into blank control group(20 cases),and Liver-soothing and spleen-invigorating group(36 cases).Compared with the blank group,the age of patients in Shugan Jianpi powder group was significantly higher(P<0.05),while the average BMI index was no significant difference(P>0.05);all groups of patients who had not menopause before endocrine treatment reached menopausal state after endocrine treatmelt.(2)There was no significant difference in endocrine therapy between the two groups,and there were more alternative estrogen receptor modulators in general.Compared with the blank control group,there were significant differences in the overall course of treatment in the Shugan Jianpi powder group(P<0.05).(3)It can be seen from the four blood lipids before and after endocrine treatment,the four blood lipids indexes(total cholesterol(TC),triglyceride(TG),low density lipoprotein cholesterol(LDL-C),high density lipoprotein cholesterol(HDL-C)in each group were all normal,and there was no significant difference in the four blood lipids among groups.But after endocrine treatment,compared with before endocrine therapy,TC,TG and LDL-C in each group increased significantly(P<0.05),while HDL-C in each group decreased,and the difference was statistically significant(P>0.05).(4)After intervention with Shugan Jianpi powder,compared with the blank control group,TC,TG and LDL-C in Shugan Jianpi powder group were lower and HDL-C was higher,but only TG,HDL-C had significant difference(P<0.05);compared with four blood lipids after endocrine treatment,Shugan Jianpi powder group had significant difference(P<0.05).The four blood lipids in the Liver-soothing and spleen-invigorating therapy group were improved to some extent,but only TC and LDL-C decreased significantly(P<0.05).There was no significant difference in the decrease of TG and the increase of HDL-C between the two groups.However,compared with the four blood lipids before endocrine therapy,the four blood lipids in Shugan Jianpi powder group had some abnormalities,and the increase of TC,TG and LDL-C had significant difference(P<0.05),but only the reduction of HDL-C had no significant difference(P>0.05).(5)The total course of treatment with drugs for soothing liver and invigorating spleen was(3.78+1.74)months,and the curative effect was 94.44%.2.Regulatory effect of soothing liver and invigorating spleen on ER a-LDLR mediated pathway in endocrine therapy-related dyslipidemia(1)From the general situation of mice in each group,there was no significant difference in the weight of mice in each group before and after the experiment(P>0.05).(2)It can be seen from the serum estrogen and progesterone of mice in each group that compared with the blank control group,the serum estrogen and progesterone levels of model group,atorvastatin group and low,medium and high dose groups of Shugan Jianpi powder all decreased,but only estrogen levels of each group decreased significantly(P<0.05),and there was no significant difference in the decrease of progesterone levels of each group(P<0.05).Compared with model control group,the serum estrogen levels of atorvastatin group and Shugan Jianpi powder low,middle and high dose groups increased,but there was no significant difference(P>0.05),while the progesterone levels of each group were similar,there was no significant difference(P>0.05).(3)Compared with the blank control group,the serum levels of TC,TG and LDL-C in the model group increased and HDL-C decreased,suggesting that the serum lipids of mice after endocrine therapy would be abnormal.Compared with the model control group,the serum levels of TC,TG and LDL-C in the low,middle and high dose groups of atorvastatin and Shugan Jianpi Fang decreased,and HDL-C decreased.The levels of TC and HDL-C in low dose group,TG in high dose group and LDL-C in low,medium and high dose group of Shugan Jianpi powder had no significant difference(P<0.05).(4)Compared with the blank control group,the expression of ERa,PR and LDLR in the liver of the model group was significantly lower than that of the blank control group,and the difference was statistically significant.Compared with the model control group,the expression of ER a,PR and LDLR in the liver of the atorvastatin group had no significant difference(P>0.05),the expression of ERa,PR and LDLR in liver of low,middle and high dose groups of Shugan Jianpi Prescription increased,and the expression of ERa and LDLR in liver of high dose group of Shugan Jianpi Prescription increased most obviously,with statistical significance(P<0.05).The expression of ER ?,PR and LDLR in liver by Western blot and immunohistochemistry was basically consistent with that by PCR.ConclusionThrough retrospective analysis of clinical cases,it is concluded that endocrine therapy is closely related to dyslipidemia in breast cancer patients,and dyslipidemia is one of the adverse reactions of endocrine therapy.After the intervention of soothing liver and strengthening spleen,the blood lipid of patients with dyslipidemia has been improved to some extent.Animal experiments in vivo have verified the correlation between soothing liver and strengthening spleen,endocrine therapy and dyslipidemia,and It 1s concluded that endocrine therapy related dyslipidemia may be mediated by ER a-LDLR pathway.Endocrine therapy can decrease the expression of ER a in vivo,whieh leads to the decrease of hormone level in vivo,and then hinders the transcription of LDLR,which leads to the decrease of the expression level,and eventually causes dyslipidemia.The method of invigorating the spleen and soothing the liver can improve the abnormal blood lipids related to endocrine therapy of breast cancer,and its mechanism is realized through ER ?-LDLR mediated pathway.It can increase the expression of ER ? and LDLR,and maintain the hormone level in vivo at a balance point which not only does not increase the risk of recurrence and metastasis of breast cancer,but also has the smallest impact on blood lipids. |
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