Research of vitamin E succinate combined with paclitaxel on the apoptosis of Her-2 over-expressing breast cancer cells

Objective： The aim of this study was to detect apoptosis rates of Her-2 overexpression breast cancer cells, which were administrated with vitamin E succinate （VES） combined with paclitaxel at different dosages, or administrated alone; to discuss the mechanism of their actions. Methods： Using immunohistochemical method to detect Her-2 expression of MDA- MB-453 cells. Using TUNEL assay to detect apoptosis rates of MDA-MB-453 ceils, with the concentrations at 10, 20 mg/L of VES and 50, 100 nmol/L of paclitaxel, and also combined together for 24 or 48 h. Then compared apoptosis action of various combinations. Results： The expression rate of 95% Her-2 was interval （63.32%, 69.60%）; VES and paclitaxel both induced apoptosis of MDA-MB-453 cells, and it is dose to time dependence. It was strongest in apoptosis at 10 mg/L VES and 100 nmol/L paclitaxel in MDA-MB-453 cells 48 h later. Conclusion： VES and paclitaxel both induced apoptosis of MDA-MB-453 cells. It is stronger when the two drugs are administrated together. The mechanism is probably related to reduction of bcl-2 expression, so as to be more sensitive to paclitaxel. Synergistic effect is also possible for the two drugs influence tumor cells in different growing phases.

Downregulation of wild-type p53 protein by HER-2/neu mediated PI3K pathway activation in human breast cancer cells: its effect on cell proliferation and implication for therapy

Overexpression and activation of HER-2/neu (also known as c-erbB-2), a proto-oncogene, was found in about 30% of human breast cancers, promoting cancer growth and making cancer cells resistant to chemo- and radio-therapy. Wild-type p53 is crucial in regulating cell growth and apoptosis and is found to be mutated or deleted in 60-70% of human cancers. And some cancers with a wild-type p53 do not have normal p53 function, suggesting that it is implicated in a complex process regulated by many factors. In the present study, we showed that the overexpression of HER-2/neu could decrease the amount of wild-type p53 protein via activating PI3K pathway, as well as inducing MDM2 nuclear translocation in MCF7 human breast cancer cells. Blockage of PI3K pathway with its specific inhibitor LY294002 caused Gl-S phase arrest, decreased cell growth rate and increased chemo- and radio-therapeutic sensitivity in MCF7 cells expressing wild-type p53. However, it did not increase the sensitivity to adriamycin in MDA-MB-453 breast cancer cells containing mutant p53. Our study indicates that blocking PI3K pathway activation mediated by HER-2/neu overexpression may be useful in the treatment of breast tumors with HER-2/neu overexpression and wild-type p53.

CORRELATION BETWEEN SERUM HER-2 ONCOPROTEIN AND PATIENTS WITH BREAST CANCER

To detect serum HER-2 oncoprotein levels in patients with operable and metastatic breast cancers, and to study the correlations between serum HER-2 level and lymph node status as well as other clinical parameters. Methods A total of 120 women were studied consisting of 10 healthy volunteers, 31 benign breast disease, 53 operable breast cancer, and 26 metastatic breast cancer patients. The levels of serum HER-2 were measured using an enzyme-liked im-munosorbent assay (ELISA). Results The mean serum HER-2 levels were 9.6 ± 1.5 ng/mL in healthy volunteers, 11.9 ± 1.6 ng/mL in benign breast disease, 13.2 ± 4.2 ng/mL in operable breast cancer, and 30.5 ± 30.8 ng/mL in metastatic breast cancer patients. The former is much lower than the latter three (P = 0.02, 0.001, 0.03, respectively). If using 15 ng/mL as a normal baseline, elevated serum HER-2 levels were observed in none of the healthy volunteers as well as patients with benign disease, but in 18.9% (10/53) operable breast cancer patients and 61.5% (16/26) metastatic patients. In patients with operable breast cancer, there was a positive correlation between serum concentrations of HER-2 and the size of primary tumor (P < 0.05), whereas there was no correlation between serum concentration and axillary lymph node or estrogen receptor status. In patients with metastatic dise-ase, there was no correlation with site of metastases (P > 0.05). Conclusion Serum HER-2 level was strongly correlated with tumor loads and clinical stages, thus acting as a promising predictor of cancer recurrence in breast cancer patients.

GENISTEIN INHIBITS EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN HER-2/NEU TRANSFECTED HUMAN BREAST CANCER MCF-7 CELLS

Objective： our previous studies have demonstrated that HER-2/neu gene expression in human breast cancer MCF-7 cells promotes angiogenesis in MCF-7 cells xenograft tumors, and genistein inhibits angiogenesis in MCF-7 cells with HER-2/neu expression xenograft tumors. Here, the effects of genistein on the expression of vascular endothelial growth factor （VEGF） in MCR-7 cells with HER-2/neu expression were further studied for exploring the molecular mechanism of anti-angiogenesis in HER-2/neu-overexpressing breast cancer by genistein. Methods： HER-2/neu-overexpressing MCF-7 cells （MCF-7/HER-2） were established by transfecting HEg-2/neu gene into HER-2/neu negative expression breast cancer MCF-7 cells. Immunocytochemical staining, western blot and reverse transcription-polymerase chain reaction （RT-PCR） were adopted to measure the expression of VEGF in MCF-7/HER-2 cells treated by genistein for 24, 48 and 72h. Results： HER-2/neu expression up-regulated VEGF mRNA and protein in MCF-7 cells, genistein decreased VEGF mRNA and protein level in MCF-7/HER-2 cells in a time-dependent manner. Conclusion： These results suggest that VEGF plays an important role in HER-2/neu gene expression promoted antiogenesis in breast cancer and genistein induced down-regulation of the expression of VEGF may be one of the molecular mechanisms of its anti-angiogenesis in HER-2/neu-overexpressing breast cancer.

Comparison of Fluorescence in situ Hybridization and Immunohistochemistry for Assessment of HER-2 Status in Breast Cancer Patients

The accurate assessment ofa proto-oncogene, human epidermal growth factor receptor-2 gene （HER-2）, is extremely important for the therapy and prognosis of breast cancer. Currently, immunohistochemistry （IHC） is the method widely used for the detection of HER-2 protein. Fluorescence in situ hybridization （FISH） has been suggested to be a golden standard assay for HER-2 amplification. This study examined the expression and amplification of HER-2 in paraffin-embedded sections of breast cancer tissues, and compared the two methods on the measurement of HER-2 status. HER-2 gene and protein were determined in breast cancer samples from 52 Chinese women by FISH and IHC respectively. The findings indicated that the HER-2 gene amplification was found in 18 cases （34.6%） by FISH and the HER-2 protein over-expression （score 3＋） in 15 cases （28.8%） by IHC. hnmunohistochemically, 28.6% of the cases scored as 2＋ and 93.3% of the cases scored as 3＋ were HER-2-positive by FISH. There was a significant correlation between the HER-2 gene amplification and HER-2 protein over-expression in breast cancer （P〈0.005）. No correlation was noted between the HER-2 gene amplification and any of the clinicopathological parameters examined, including age, menopausal status, menarche age, tumor size, histological tumor type, histological grade, lymph node status, and the expression of ER and PR. It was concluded that the detection of HER-2 gene amplification in breast cancer by FISH is valuable and can compare with HER-2 protein detection by IHC.

HER-2 expression after neoadjuvant chemotherapy of the breast cancers

Objective:The aim of this study was to study changes of HER-2 expression after neoadjuvant chemotherapy in the breast cancer cases.Methods:One hundred and thirty-seven female patients with primary breast cancers,who received neoadjuvant chemotherapy,underwent core needle puncture and Mammotome biopsy before chemotherapy,and the biopsy results were used as the basis of histological diagnosis,fluorescence in situ hybridization (FISH) was performed to test HER2 status of tumor tissues before and after chemotherapy.All patients underwent FEC,TE,or AC neoadjuvant chemotherapy of 2-6 cycles before surgery.Results:Twenty-two patients were positive according to FISH test among 137 preoperative patients,8 patients achieved pathological complete remission after chemotherapy (three HER-2 positive patients and five negative patients),91 patients achieved partial remission,24 patients were stable,and 14 cases were invalid.Twenty-two patients were positive according to FISH test (8 patients with pathological complete remission did not undergo test),and positive patients still expressed positively after chemotherapy before neoadjuvant chemotherapy.Three negative patients were converted to be positive,and changes before and after chemotherapy had no statistical difference (P>0.05).Conclusion:Neoadjuvant chemotherapy makes no influence on patients with HER-2 positive expression,while patients with negative expression can be converted to be positive,but without significant difference.

HER-2,P53 and Hormonal Receptors Protein Expression as Predictive Factors in Breast Cancer Prognosis

OBJECTIVE Breast cancer is a heterogeneous disease with vari-able biological and clinical characteristics.We conducted a studyto evaluate P53,HER-2/neu and hormonal receptor expression aspredictors of prognosis in breast cancer.METHODS In a prospective study,we recruited 81 consecutivepatients with primary operable breast cancer who were treatedwith mastectomy followed by locoregional radiotherapy or che-motherapy and studied the presence of P53,HER-2/neu andhormonal receptors (ER/PR) expression in tumor tissues by im-munohistochemical staining.Associations between these markersexpression and clinical outcomes,including local and regionalrecurrence and metastasis were evaluated.Statistical analysis wasperformed with the SPSS software.RESULTS The mean time of follow-up was (47.3±4.6) months.Expression of P53,HER-2/neu,Estrogen receptors and progester-one receptors were observed in 31.1%,38.5%,31.8% and 51.7% ofthe patients,respectively.P53,HER-2/neu and Negative ER statuswere potent predictors of local-regional recurrence (P=0.034,0.038,0.044,respectively).Also HER-2/neu,Negative ER and NegativePR status were strong predictors of metastasis (P=0.001,0.042,0.054,respectively).CONCLUSION P53 and HER-2/neu expression and also steroidreceptors status (ER/PR status) have an important role in predict-ing the outcome of breast cancer and thus may be of value in se-lecting suitable therapeutic strategy and determining prognosis inthese patients.

Impressive Objective Response to Nab-Paclitaxel plus Trastuzumab as Fifth Line Therapy in an Elderly HER-2 Positive Breast Cancer Patient

Background: Agent targeting HER-2 pathway plus chemotherapy has represented a major progress in the management of patients with breast cancer. However, the role of late-line treatment in heavily pretreated patients is still largely unclear. In the last decade, nab-paclitaxel has shown significant activity and good toxicity profile in metastatic breast cancer. Case Presentation: We report the case of a 76-year-old Caucasian woman with metastatic HER-2 positive ductal infiltrating breast carcinoma treated with a combination of weekly nab-paclitaxel and trastuzumab as fifth-line therapy. She had previously received first-line paclitaxel and trastuzumab, second-line vinorelbine and trastuzumab, third-line TDM1 and fourth-line oral capecitabine and lapatinib. Clinical and radiological staging showed progression at bone, skin and soft-tissue. The patient received weekly nab-paclitaxel plus trastuzumab. Massive objective response was clinically and PET documented which lasted 8 months. Tolerance to treatment was fairly good as well as cardiac safety. Conclusion: To the best of our knowledge, this is the first reported case of efficacy of nab-paclitaxel in combination with trastuzumab as fifth-line of treatment in a patient with metastatic HER-2 positive breast cancer.

Relationship between expression of ER, PR, Her-2, Ki-67 and neoadjuvant chemotherapy effect in breast cancer

Objective: The purpose of the study was to investigate the relationship between the expression of estrogen receptor(ER), progestogen receptor(PR), human epidermal growth factor receptor(Her-2), Ki-67 and the effect of neoadjuvant chemotherapy in breast cancer. Methods: The expression of ER, PR, Her-2 and Ki-67 in 45 breast cancers which received neoadjuvant chemotherapy was detected by immunohistochemistry. Results: The effective rates in ER negative and PR negative groups were higher than those in ER positive and PR positive groups(83.3% vs 59. 4%, 82.4% vs 60.6%). There was no significant difference of the effective rate between Her-2 overexpressed group and Her-2 non-overexpressed group(81.8% vs 64.1%), and the same thing happened between Ki-67 negative group and Ki-67 positive group(67.7% vs 63.2%). Conclusion: In the patients with breast cancer, ER, PR negative ones were more sensitive to neoadjuvant chemotherapy. These patients may get more benefits from chemotherapy. ER, PR could be feasible markers for predicting the effective rate of neoadjuvant chemotherapy.

Detection of HER-2/neu Amplification on Fine Needle Aspirates of Breast Cancer Using Fluorescence in Situ Hybridization

The accuracy of diagnostic assays for HER-2/neu in breast cancer is extremely important as HER-2/neu status is essential in tailoring adjuvant and/or neoadjuvant treatment in every patient. FNAC is widely practiced in Egypt in preoperative diagnosis of breast cancer for its low cost and high diagnostic accuracy. Since the determination of HER-2/neu protein expression on cytological preparations was previously found to be unreliable for clinical use, we opted for the assessment of HER-2/neu status in fine needle aspirates using FISH. The main objective of this study was to evaluate the reliability of HER-2/neu status assessment by FISH on fine needle aspirates of breast cancers by comparing the results with IHC and FISH on FFPE tissue sections obtained from corresponding surgically resected specimens. Fine needle aspirates from 40 breast cancer patients with pathologically confirmed breast cancer were included in the study. They were submitted for HER-2/neu evaluation by FISH. After surgery, the corresponding FFPE sections were evaluated for HER-2/neu by FISH and by IHC. FNAs from 11 cases proved to be amplified by FISH, while 29 cases were not amplified. Apart from two cases that showed lack of signals, all specimens evaluated by FISH on the corresponding FFPE sections showed matched results. The Measurement of Agreement between FISH on FNAs and FISH on FFPE sections was 86.7%, while that between FISH on FNAs and IHC was 72.5%. The high concordance rate in the present study between FISH evaluation of HER-2/neu gene amplification on FNAC samples and their corresponding FFPE samples indicate that FISH may be a reliable technique for HER-2/neu assessment on FNAs. Furthermore, FISH on FNAs gave us better hybridization signals than their corresponding FFPE tissue sections. Finally, we also conclude that all score (2+) cases by IHC should be reevaluated by FISH which is crucial for the patient management.

Evaluation of Tobacco Use and Her-2 Receptor Expression in Breast Cancer in an Ethnically Diverse Inner-City Population

Background: Tobacco is linked to most cancers however despite overwhelming biological plausibility and decades of epidemiological studies, no association has been established between tobacco and breast cancer. Although estrogen receptor status has been looked at as a variable there has been no evaluation of the role of Her-2 and smoking in breast cancer. Methods: Review of records from patients treated at the University of Miami/Jackson Memorial Hospital from 1998-2012. The incidence of smoking and Her-2 expression in1255 women was evaluated. Data was analyzed by age, race, ethnic group, menopausal status, tumor stage, and ER/PR/Her-2 receptor status. Results: 1255 charts were analyzed with 1094 having full information. Overall rate of Her-2 expression 18.1%. The rate of Her-2 expression was 21.4% in smokers and 17.0% in non-smokers (p = 0.10). The rate of Her-2 expression was 10.8% in Caucasian smokers and 9.8% in Caucasian non-smokers (p = 0.88);24.5% in smokers of African descent and 17.3% in non-smokers of African descent (p = 0.24);22.9% in Latino smokers and 17.4% in Latino non-smokers (p = 0.10). The rate of Her-2/ER expression was 9.4% in smokers and 7.9% in non-smokers (p = 0.42);5.4% in Caucasian smokers and 4.9% in Caucasian non-smokers (p = 0.916);12.2% in smokers of African descent and 5.9% in non-smokers of African descent (p = 0.11);9.5% in Latin smokers and 8.8% in Latin non-smokers (p = 0.77). Conclusions: We found non-statistically significant positive associations in all analyses between Her-2 expression with or without ER expression and tobacco exposure when analyzed by ethnicity.

Chidamide Combined with Paclitaxel Liposome for the Treatment of Advanced HER2-negative Breast Cancer in Clinical Study

The purpose of this study was to investigate the efficacy and safety of chidamide combined with paclitaxel liposome in the treatment of advanced HER-2-negative breast cancer.First,41 patients with advanced HER-2-negative breast cancer who had received two chemotherapy regimens from May 2017 to November 2017 were randomly selected to receive chidamide combined with paclitaxel liposome treatment(observation group,n=20)or placebo combined with paclitaxel liposome treatment(control group,n=21).The treatment scheme of the observation group was oral chidamide 30mg twice a week for 2 months.In addition,on day 1,the patients were given paclitaxel liposome orally and intravenously administered with 175 mg/m2 for 1 cycle for 21 days and 3 cycles of chemotherapy.The treatment scheme of the control group was oral placebo 30 mg twice a week for 2 months.In addition,the method of paclitaxel liposome administration was the same as the observation group.The response rate(RR),disease control rate(DCR),and progression-free survival(PFS)were compared between the two groups.The results showed that all the 41 patients could be evaluated.In the observation group,CR5,PR7,SD5 and PD3 were obtained.RR was 60.0%and DCR was 85.0%.In the control group,CR3,PR3,SD5 and PD10 were obtained.RR was 28.6%and DCR was 52.4%.RR and DCR in the observation group were better than those in the control group,and the difference was statistically significant(P<0.05).The median PFS of the observation group was 5.2 months,longer than that of the control group(3.1 months,P<0.05).The main adverse reactions in the two groups were gastrointestinal reactions and bone marrow suppression,with grade 1~2 as the main ones.The incidence of leukopenia,thrombocytopenia and nausea and vomiting in the observation group was higher than that in the control group(P<0.05).Therefore,the chidamide combined with paclitaxel liposome is effective in the treatment of advanced HER-2-negative breast cancer,and the adverse reactions can be tolerated.

Enhanced immuno-detection of shed extracellular domain of HER-2/neu

HER-2/neu oncogene is over-expressed and amplified in patients associated with metastatic breast cancer. An increased level (>15 ng/mL) in the shed extracellular domain (sECD-HER 2/neu) is indicative of the potential presence and as-sociated progression of this disease. A fluo-rescent ELISA incorporating the newly devel-oped ALYGNSA antibody-orientation system revealed a 10-fold increase in sensitivity (≤0.63 ng/mL) of sECD-HER 2/neu when compared to a control standard ELISA kit (≤7.5 ng/mL). This enhanced mode of detection has the potential to not only address breast and other cancers per se but also permit an in depth evaluation of “shed extracellular domains”, in general, and the role of these “proteolytic derived factors” in physiological signalling at normal levels.

Study on the high risk factors related to different metastatic sites of advanced breast cancer

Objective:Several studies indicated that many factors have relationship with the metastatic sites of advanced breast cancer.This retrospective study investigated the high risk factors which related to the different metastatic sites of stage IV breast cancer.Patients and methods:From January 2003 to December 2005 a total of 387 consecutive breast cancer patients were retrospectively analyzed.The relationships between different categorical variables and breast cancer were identified by Chi-square tests.Results:The high risk factors of metastatic breast cancer included the overexpression of HER-2 and lymph nodes invasion.The overexpression of HER-2 and lymph nodes invasion had a significantly difference between metastatic breast cancer and breast cancer without metastasis(P=0.018,P<0.001,respectively).As for metastatic breast cancer patients with only one single metastatic organ,the overexpression of HER-2 had a significantly high positive rate in patients with visceral metastases when compared with bone metastasis(P=0.045).Conclusion:The overexpression of HER-2 and lymph nodes invasion significantly influenced the metastasis of breast cancer.Overexpression of Her-2 was high risk factors for breast cancer developed to visceral metastases disease.

Screening of miRNAs associated with lymph node metastasis in Her-2-positive breast cancer and their relationship with prognosis

The aim of this study was to identify some biomarkers for predicting lymph node metastasis and prognosis of human epidermal growth factor receptor 2(Her-2)-positive breast cancer(BC). We analyzed correlations between micro RNAs(mi RNAs) and the prognosis of patients with BC based on data collected from The Cancer Genome Atlas(TCGA) database. The expression levels of mi R-455, mi R-143, and mi R-99 a were measured in clinical samples of Her-2-positive BC patients with different degrees of lymph node metastasis. We investigated the impacts of overexpressed mi R-455 on the proliferation and invasiveness of MDA-MB-453 cells and measured its effects on the expression of long non-coding RNA(lnc RNA) metastasis-associated lung adenocarcinoma transcript 1(MALAT1) by quantitative real-time polymerase chain reaction(q RT-PCR). The expression of mi R-455 was significantly and positively correlated to the prognosis and overall survival(OS) of the BC(P=0.028), according to TCGA information. The expression level of mi R-455 was positively correlated with OS and relapse-free survival(RFS) of patients with Her-2-positive BC, and was negatively correlated with the number of metastatic lymph nodes(P<0.05). Transwell assay suggested that MDA-MB-453 cells became much less invasive(P<0.01) after being transfected with mi R-455 mimics. During the q RT-PCR, the expression level of MALAT1 declined significantly after transfection(P<0.01). Overexpressed mi R-455 significantly inhibited the proliferation and migration of MDA-MB-453 cells and the expression of MALAT1. We conclude that mi R-455 may be a useful potential biomarker for forecasting lymph node metastasis and the prognosis of Her-2-positive BC patients. mi R-455 may play an important role in lymph node metastasis of BC by interacting with MALAT1.

HER-2/EGFR, the major targets for anti-metastasis effect of tetraarsenic oxide on SKBR3 breast cancer cells

Breast cancer is one of the most common female malignant tumors in the world. Although many therapeutic methods for HER-2 positive breast cancer have been developed, the drug resistance and distant metastasis still remain. Tetraarsenic oxide（As_4O_6） has been demonstrated with an anticancer effect on squamous cell carcinoma and cervical cancer. However, there is no report about the relationship between As_4O_6 and HER-2 positive breast cancer. In the present study, we detected the inhibitory efficacy and mechanism of As_4O_6 on the migration and invasion of SKBR3 breast cancer cells using molecular biological methods. The wound-healing assay, matrigel migration assay, transwell invasion assay and cell adhesion assay were used to assess the migration, invasion and adhesion of SKBR3 cells intervened by As_4O_6. Meanwhile, the reverse transcription-PCR and western blotting were performed to investigate the mechanism of As_4O_6 on the migration and invasion of SKBR3 breast cancer cells. The results demonstrated that As_4O_6 could efficiently inhibit the migration and invasion of SKBR3 cells, the HER-2 positive breast cancer cells, and the adhesion of SKBR3 cells was decreased after As_4O_6 treatment. The mechanism revealed that As_4O_6 anticancer efficacy was related to HER-2/EGFR pathways. As_4O_6 exerted its inhibitory effects on migration and invasion in HER-2 positive breast cancer cells by regulating the factors（EGFR, HER-2, Akt, MMP-9） in HER2/ EGFR signaling pathway and other key molecules. In conclusion, the present study indicated that As_4O_6 inhibited the invasion and migration process of HER-2 positive breast cancer SKBR3 cells by negatively regulating the HER-2/EGFR-mediated signaling pathway. These data provided evidence that As_4O_6 might serve as potential anti-metastasis drug for clinical treatment of breast cancer.

The mechanism of BRCA1 participate sporadic breast carcinomas genesis

Objective To elucidate the BRCA1 participated mechanism of genesis and development of sporadic breast cancer through detect the statues of BRCA1 and analysis the relationship with the pathologic and clinic parameters.Methods BRCA1 statues were respectively analyzed in frozen samples or paraffine fixed sporadic breast carcinoma and benign breast tissues by three methods:protein expression by immunohistochemistry(IHC),the methylation of BRCA1 promoter by methylation specific PCR(MSP),gene copy number by interphase fluorescence in situ hybridization(FISH).Results 14.2%(29/204)cases were detected hypermethylation of BRCA1 promoter in sporadic breast cancer.BRCA1 mean copy number in sporadic breast cancer(1.70±0.14)less than those in benign tissues(2.03±0.08,P<0.05),and in sporadic breast cancer with hypermethylation of BRCA1(1.62±0.09)significantly less than in those without hypermethylation(1.84±0.26,P<0.05).The loss copy related to the methylation of BRCA1 promoter.There were significant of 41.1%(88/214)cases no BRCA1 nuclei expression in sporadic breast cancers.Loss expression of BRCA1 had significant correlation with higher histological stages,axillary's lymph nodal metastasis(P<0.01),lower expression of ERα,and overexpression of HER-2 protein(P<0.01).Conclusions There are BRCA1 methylations,loss BRCA1 gene copy and loss protein expression in the sporadic breast cancer,the three statues of BRCA1 is correlated to each other;and the loss expression of BRCA1 protein related to part of pathology and clinic parameters.

Injectable“cocktail”hydrogel with dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic effect

The combination of the first-line standard chemotherapeutic drug doxorubicin hydrochloride(DOX)and the molecular-targeted drug Herceptin(HCT)has emerged as a promising strategy for human epidermal growth receptor 2(HER-2)overexpressing breast cancer treatment.However,insufficient drug accumulation and severe cardiotoxicity are two major challenges that limit its clinical application.Herein,an in situ forming gold nanorods(AuNRs)-sodium alginate(ALG)hybrid hydrogel encapsulating DOX and HCT was engineered for tumor synergistic therapy involving injectable,dual-stimuli-responsive drug release,photothermal ablation,and drug-antibody synergistic therapy.The photothermal agent AuNRs,anticancer drug DOX,and anticancer antibody HCT were mixed in ALG solution,and after injection,the soluble ALG was quickly transformed into a hydrogel in the presence of Ca^(2+)in the body.Significantly,the hybrid hydrogel exhibits an extremely high photothermal conversion efficiency of 70%under 808 nm laser irradiation.The thermal effect can also provide photothermal stimulation to trigger the drug release from the gel matrix.In addition,the drug release rate and the releasing degree are also sensitive to the pH.In vitro studies demonstrated that the PEI-AuNR/DOX/HCT/ALG hydrogel has facilitated the therapeutic efficiency of each payload and demonstrated a strong synergistic killing effect on SK-BR-3 cells.In vivo imaging results showed that the local drug delivery system can effectively reduce the nonspecific distribution in normal tissues and increase drug concentration at tumor sites.The proposed hydrogel system shows significant clinical implications by easily introducing a sustainable photothermal therapy and a potential universal carrier for the local delivery of multiple drugs to overcome the challenges faced in HER-2 overexpressing cancer therapy.