ABSTRACT
Human epidermal growth factor receptor-2 （HER-2）-positive breast cancer has higher predilection to metastasize and invade other organs， leading to poor prognosis. The anti-HER-2 drugs， such as trastuzumab， pertuzumab， and trastuzumab emtansinehas， can remarkably prolong the disease free survival （DFS） of patients. However， frequent multidrug resistance， tumor recurrence and metastasis， and adverse reactions such as cardiotoxicity and gastrointestinal discomfort caused by adjuvant therapy are still challenges for the treatment of HER-2-positive breast cancer. The understanding of breast cancer in traditional Chinese medicine （TCM） has a long history. In thousands of years of inheritance and innovation， a standardized treatment system with TCM characteristics has been gradually formed， which shows unique advantages and significant curative effects in breast cancer treatment. The treatment principles of ''treatment based on syndrome differentiation''， ''treatment based on stages and types''， ''treatment according to individual conditions''， and ''treatment of different viscera and viscera based on the toxin and pathogen'' are closely related to the precise treatment concept. In view of the challenges in the treatment of HER-2-positive breast cancer， such as multidrug resistance， tumor recurrence and metastasis， cardiotoxicity， and gastrointestinal discomfort， this paper summarizes the characteristics of TCM in reversing the multidrug resistance， inhibiting tumor recurrence and metastasis， prolonging DFS， improving prognosis， reducing adverse reactions caused by adjuvant therapy， and improving the quality of life after breast cancer surgery according to the principles of reinforcing healthy Qi and eliminating pathogen， and treatment based on syndrome differentiation. This article is expected to serve as a reference for TCM treatment of HER-2 positive breast cancer.
ABSTRACT
Human epidermal growth factor receptor 2 (HER2)-targeted therapy has greatly improved the prognosis of HER2-positive breast cancer. HER2-targeted therapy combined with chemotherapy dominated by trastuzumab+ pertuzumab is important in the neoadjuvant therapy, postoperative adjuvant therapy and late-stage standard treatment for HER2-positive breast cancer. Antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) have further improved the efficacy of therapy. However, advanced breast cancer will eventually get a recurrence or drug resistance. HER2-positive breast cancer is characterized by moderate immunogenicity with the presence of large tumor-infiltrating lymphocytes (TILs), which provides a theoretical basis for immunotherapy. The application of HER2-targeted cancer vaccines and immune checkpoint inhibitors is promising and would offer more treatment options for the patients.
ABSTRACT
OBJECTIVE@#To investigate the effect of metformin on the proliferation and apoptosis of HER-2-positive breast cancer cell line SKBR3 and explore the possible mechanism of its action.@*METHODS@#SKBR3 cells were treated with different concentrations (20-120 μmol/L) of metformin, and the changes in cell proliferation and colony formation ability were assessed using CCK-8 assay and crystal violet staining, respectively. Flow cytometry was performed to analyze cell apoptosis and cell cycle changes. Real-time fluorescent quantitative PCR (qRT-PCR) was used to detect mRNA expressions of YAP, TAZ, EGFR, CTGF, CYR61, E-cadherin, N-cadherin, vimentin and fibronectin in the treated cells, and the protein expressions of YAP and TAZ were detected using Western blotting; immunofluorescence assay was used to observe YAP/TAZ nuclear translocation in the cells.@*RESULTS@#Metformin treatment significantly inhibited the proliferation of SKBR3 cells (P < 0.05) in a concentration- and time-dependent manner. The results of flow cytometry showed that metformin significantly promoted apoptosis and caused cell cycle arrest at G1 phase in SKBR3 cells. Metformin treatment significantly down-regulated the mRNA expressions of YAP, TAZ, EGFR, CTGF and CYR61, N-cadherin, vimentin and fibronectin (P < 0.05) and up-regulated the expression of E-cadherin (P < 0.05); Western blotting results showed that YAP and TAZ protein expressions were significantly down-regulated in the cells after metformin treatment (P < 0.05). Immunofluorescence assay revealed that metformin treatment caused the concentration of YAP and TAZ in the cytoplasm, and significantly reduced their amount in the cell nucleus.@*CONCLUSION@#Metformin can inhibit proliferation and promote apoptosis and epithelal-mesenchymal transition of HER-2 positive breast cancer cells possibly by that inhibing YAP and TAZ expression and their nuclear localization.
Subject(s)
Apoptosis , Cadherins , Cell Proliferation , ErbB Receptors , Fibronectins , Metformin/pharmacology , Neoplasms , Protein Serine-Threonine Kinases , RNA, Messenger , Transcription Factors/metabolism , VimentinABSTRACT
Objective:To explore the expression and clinical significance of KIF20A in HER2-positive breast cancer.Methods:The clinicopathological characteristics of 82 cases of HER2-positive breast cancer were retrospectively analyzed. The expression of KIF20A in tissues was detected by immunohistochemical method, and the expression of KIF20A in HER2 overexpression breast cancer and its relationship with clinicopathological characteristics were analyzed. The mRNA level of KIF20A in HER2-positive breast cancer tissues and normal tissues adjacent to cancer were analyzed by bioinformatics methods.Results:The positive expression of KIF20A was in the nucleus, forming brown-yellow particles. In HER2-positive breast cancer tissues, the positive high expression rate of KIF20A is 57.3%, while it is mainly low or no expression in the adjacent tissues. The high expression of KIF20A is significantly correlated with tumor size and pTNM stage, while the correlation with age and tumor grade is not statistically significant. The results of bioinformatics analysis suggest that the high expression of KIF20A in invasive breast cancer is significantly related to poor disease-free survival.Conclusions:KIF20A is abnormally expressed in HER2-positive breast cancer, which is related to the tumor grade and pTNM stage of HER2 overexpression breast cancer, and the high expression of KIF20A indicates a poor prognosis.
ABSTRACT
Objective To explore the evaluation value of MRI parameters and immunohistochemistry in the neoadjuvant chemotherapy (NAC)for the HER-2 positive breast cancer.Methods 7 6 patients with locally advanced HER-2 positive breast cancer were analyzed retrospectively.According to the postoperative pathology,patients were divided into pathological complete response (PCR)group and non-PCR (Non-PCR)group.First,univariate and multivariate Logistic regression analysis were used to analyze the predictors of PCR,and then we assessed the evaluation value of the assessment model which was built on multivariate logistic regression.Results Univariate regression analysis showed that menstrual status,ER expression,K-i 67 expression,ADC value,tumor diameter, ΔADC%(NAC2－NAC0),ΔD%(NAC0－NAC2) had predictive value for PCR;the parameters ΔADC% and ΔD%,the expression of ER and K-i 67 were independent predictors of PCR based on multivariate Logistic regression analysis.The AUC of the assessment model model was 0.873.Conclusion Based on the heterogeneity of breast cancer,combine MRI with immunohistochemistry parameters could improve the prediction in the middle of NAC,and provide imaging basis for the adj ustment of follow-up chemotherapy regimen.
ABSTRACT
Objective The aim of current study was to evaluate the effect of growth differentiation factor 15( GDF-15) on predicting and monitoring the cardiotoxicity of epirubicin/cyclophosphamide-docetaxel-trastuzumab(EC-D-T)in the treatment of HER-2 positive breast cancer patients. Methods Seventy-three patients with HER-2 positive breast cancer who received EC-D-T adjuvant therapy were enrolled. Serum levels of GDF-15,cardiac troponin I(cTnl)and amino terminal brain natriuretic peptide precursor(NT-proBNP)were measured before adjuvant therapy(M0)and after adjuvant therapy at 3 months(M3 ),6 months(M6 ),9 months(M9 ),12 months(M12 )and 15 months(M15 ). At the same time,patients underwent echocardiography at various time points to assess the left ventricular ejection fraction(LVEF). The cardiotoxicity of this study was defined as:(1)LVEF level decreased by ≥10% after treatment and the absolute value of LVEF was below 53% (normal);(2) heart failure,acute coronary syndrome or severe life-threatening heart rate abnormal. Results After initiation of EC-D-T treatment,the level of LVEF gradually decreased. Dur-ing the whole study,a total of 21(28. 8% )patients developed cardiotoxicity. At the same time,patients with cardiotoxicity had signifi-cantly higher levels of GDF-15 at M0 and cTn1 at various time points than those without cardiotoxicity. The level of ProBNP was comparable to those without cardiotoxicity. In addition,Univariate logistic regression analysis showed that baseline GDF-15 might af-fect the risk of cardiotoxicity. Multivariate logistic regression analysis showed that only cTnl level was an independent predictor for the risk of cardiotoxicity, while NT-proBNP level did not predict the risk of cardiotoxicity. Conclusion The incidence of cardiotoxicity in patients with HER-2 positive breast cancer after receiving EC-D-T is high,and GDF-15 can predict and monitor the risk of cardiotoxicity.
ABSTRACT
Objective To analyze and validate the key molecular targets correlated with the overall survival of patients with HER2-positive breast cancer.Methods First,the survival time and transcriptome data of patients with HER2-positive breast cancer in stage Ⅰ / Ⅱ and Ⅲ/Ⅳ were downloaded from the TCGA database.The significantly differential genes between overall survival ＜2 years and ＞8.5 years in stage Ⅰ / Ⅱ were picked out by edgeR package,and the pathways were enriched by KEGG.Similarly,the differential genes between overall survival ＜2 years and ＞7 years in stage Ⅲ/Ⅳ were analyzed.Furthermore,KEGG pathway analysis was performed using the differential genes overlapped by stage Ⅰ /Ⅱ and Ⅲ/Ⅳ.Second,the relationships between the expression levels of key node genes and other genes in enriched pathway and the overall survival of patients with HER2-positive breast cancer were validated by KMplot database.Last,the correlation between the activity of pathway enriched in KEGG and the resistance to anti-HER2 treatment was validated in HER2-positive breast cancer cell line BT474.Results In patients with stage Ⅰ / Ⅱ HER2-positive breast cancer whose overall survival was ＜2 years,PI3K/AKT was the 9th signaling pathway enriched by up-regulated differential genes.In patients with stage Ⅲ/Ⅳ whose overall survival was ＜2 years,PI3K/AKT was the 2nd signaling pathway enriched by up-regulated differential genes.Furthermore,PI3K/AKT was the first signal pathway enriched by the overlapping upregulated genes of patients in stage Ⅰ / Ⅱ and Ⅲ / Ⅳ whose overall survival was ＜2 years.Patients with high expression of PI3K and AKT (key node genes) or CFAP221 and COL4A6 (other genes) of PI3K/AKT pathway had shorter overall survival than those with low expression.PI3K inhibitors could enhance the growth inhibitory effect of HER2 small molecule inhibitor on HER2-positive breast cancer cell line BT474.Conclusions The overexpression of PI3K/AKT pathway is associated with the shorter overall survival in HER2-positive breast cancer patients,and associated with anti-HER2 resistance in HER2-positive breast cancer cell line.
ABSTRACT
@#Objective To investigate the inhibitory effect and molecular mechanism of delphinidin (Dp) on HER-2 positive breast cancer. Methods The HER-2 positive breast cancer cells (MDA-MB-453 and BT-474) were treated with different concentrations of delphinidin (10，20，40，80 and 160 μmol/L) for 48 hours. The same concentration of DMSO was used as the solvent control. CCK-8 method was used to measure the effect of Dp on cell activity, and half maximal inhibitory concentration (IC50) was calculated to determine the concentration of subsequent experiments. The cells were treated with different concentrations of Dp (20, 40 and 80 μmol/L) for 48 hours. HE staining was used to observe the cell morphological changes. Flow cytometry was used to analyze the cell cycle. Cell apoptosis rate was detected by TUNEL assay. The phosphorylation levels of NF - κB signaling pathway related proteins were determined by Western blot assay. Results Delphinidin inhibited the proliferation of MDA-MB-453 and BT-474 in the concentration ranges of 10，20，40，80 and 160 μmol/L (IC50: 41.02 and 60.97 μmol/L). In the concentrations of 20，40 and 80 μmol/L, compared with the control group, it was found that some cells were detached, floated and lysed, and the cell volume was decreased, the proportion of cells in G2/ M phase and the apoptosis rate were increased in DP treatment groups. Compared with the control group, the expression levels of p-NF-κB/p65, p-IκBα, p-IKKα/β and p-PKCα were significantly decreased in the 40 and 80 μmol/L Dp treatment groups, while the expression levels of IκBα, IKKα, IKKβ and PKCα were increased in the Dp treatment groups (P＜0.05). Conclusion Delphinine can inhibit the proliferation of breast cancer cells by blocking the NF-κB signaling pathway and inducing the G2/M cycle arrest and apoptosis of MDA-MB-453 and BT-474 cells. Key words：receptor, epidermal growth factor; antineoplastic agents, phytogenic; breast neoplasms; cell cycle; delphinidin;HER-2 positive breast cancer; NF-κB signaling pathway
ABSTRACT
OBJECTIVE:To observe the effect of trantuzumab combined with preoperative adjuvant chemotherapy in the treat-ment of human epidermal growth factor receptors 2 (Her-2) positive breast cancer,and to investigate its clinical value. METH-ODS:80 patients with Her-2 positive breast cancer were selected and randomly divided into observation group and control group, with 40 cases in each group. The control group received routine preoperative adjuvant chemotherapy+modified radical mastectomy for Her-2 positive breast cancer;observation group was additionally treated with trastuzumab intravenously before operation,initial dose of 4 mg/kg,followed by 2 mg/kg,once a week,for consecutive 3 weeks,on the basis of control group. The effects of two regimen on the expression of HER-2,CD-34,MGA,E-cadherin and GCDFE-15 in Her 2 positive breast cancer focus were com-pared between 2 groups. ADR and follow-up survey were recorded. RESULTS:Compared with before chemotherapy,the expres-sion of HER-2(+)in observation group increased significantly,while that of HER-2(+ + +)decreased significantly;MGA posi-tive rate and GCDFP-15 positive rate decreased significantly while E-cadherin positive rate increased significantly;MDV of CD34 expression decreased significantly,with statistical significance(P0.05). CONCLUSIONS:Trastuzumab combined with preoperative adjuvant chemotherapy have good clinical efficacy and safety,and it can effectively reduce related indicator of Her-2 positive breast cancer focus. So it has positive significance in reducing recurrence and metastasis of breast cancer.