Treatment Of Drug-resistant Breast Cancer Research Articles

A facile, flexible, and multifunctional thermo-chemotherapy system for customized treatment of drug-resistant breast cancer

Anticancer drug resistance invariably emerges and poses a significant barrier to curative therapy for various breast cancers. This results in a lack of satisfactory therapeutic medicine for cancer treatment. Herein, a universal vector system for drug-resistance breast cancer was designed to meet the needs of reversed multidrug resistance, thermo-chemotherapy, and long-term drug release behavior. The vector system comprises polycaprolactone (PCL) nanofiber mesh and magnetic nanoparticles (MNPs). PCL has excellent biocompatibility and electrospinning performance. In this study, MNPs were tailored to be thermogenic in response to an alternating magnetic field (AMF). PCL nanofiber can deliver various chemotherapy drugs, and suitable MNPs encapsulated in the nanofiber can generate hyperthermia and synergistic effect with those chemotherapy drugs. Therefore, a more personalized treatment system can be developed for different breast malignancies. In addition, the PCL nanofiber mesh (NFM) enables sustained release of the drugs for up two months, avoiding the burden on patients caused by repeated administration. Through model drugs doxorubicin (DOX) and chemosensitizers curcumin (CUR), we systematically verified the therapeutic effect of DOX-resistance breast cancer and inhibition of tumor generation in vivo. These findings represent a multifaceted platform of importance for validating strategic reversed MDR in pursuit of promoted thermo-chemotherapeutic outcomes. More importantly, the low cost and excellent safety and efficacy of this nanofiber mesh demonstrate that this can be customized multi-function vector system may be a promising candidate for refractory cancer therapy in clinical.

Abstract 1860: NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer

Abstract Resistance to cyclin D-cdk4/6 inhibitors (CDK4/6i) is frequently caused by compensatory CDK2 activity. We have developed a novel strategy to kill CDK4i resistant tumor cells using a therapeutic liposomal:peptide formulation, NP-ALT, to inhibit the tyrosine phosphorylation of p27Kip1(CDKN1B), which in turn inhibits both CDK4/6 and CDK2. IpY is specific for p27, and this reduces toxicity relative to that seen with the small molecule ATP-competitive CDK4/6i or CDK2i. NP-ALT blocks DNA replication in HR+ breast cancer (BC) cells and mouse models, but unlike CDK4/6i or CDK2i treatment, it induces ROS-dependent necroptosis to kill the tumor cells. This RIPK1/RIPK3-dependent cell death is more specific for HR+ lineages, but the combination of NP-ALT and palbociclib in TNBC cells causes synergy to induce necroptosis. We found that NP-ALT was still able to induce necroptosis in cell lines resistant to palbociclib, including those harboring genetic perturbations detected clinically in patients resistant to palbociclib. HR+ cell lines engineered to overexpress CDK6, FGFR, cyclin E, or cyclin D or ones that have loss of FAT1 or RB were still sensitive to NP-ALT. We tested other CDK2i, including CYC065, a CDK2/9 inhibitor and PF-06873600, a CDK4/6/2 inhibitor, and and found that while they were able to block DNA replication, only NP-ALT was able to induce ROS-dependent death in the resistant lines. We have shown that IpY reduces tumor volumes in resistant in vivo models as well, without causing adverse effects. Thus, NP-ALT and p27 targeting has several differentiators, which might provide clinical advantages: a) its low toxicity due to the tight specificity of the peptide for the p27 target and b) its ability to kill tumor cells as opposed to just causing cytostasis. Concarlo is currently developing NP-ALT into a therapeutic lead for the treatment of drug-resistant breast cancer. Citation Format: Stacy Wister Blain, Arianna Chand, Lina Pedraza-Ortiz, Allison VanInwegen, Lingyu Yan, Yun Wu, Grace Chen, Irina Jilishitz. NP-ALT, a liposomal:peptide drug, blocks p27Kip1 phosphorylation to cause cell death in CDK4i-resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1860.

Multifunctional Nanotherapeutics for Drug-Resistant Breast Cancer

Tumors are inherently resilient and always develop drug-resistance, leading to poor patient therapy effect. With the developing of sophisticated analytical tools, some novel strategy on improving targeting of anti-cancer delivery is developed to better thwart drug-resistance. This report demonstrates a multilayered nano-system to serve as a multifunctional platform for the treatment of drug-resistant breast cancers. This nano-system is composed of a poly (lactic-co-glycolic acid) core, a liposome second layer, and a hyaluronic acid outmost layer. The different types of drug, loaded in different layers, are released in a controlled and sequential manner upon internalization and localization. This recreated the time-staggering effect necessary for maximal efficacy.

Folic acid conjugated chitosan encapsulated palladium nanoclusters for NIR triggered photothermal breast cancer treatment

This study developed folic acid (FA) conjugated chitosan (CS) encapsulated rutin (R) synthesized palladium nanoclusters (Pd NCs) for NIR triggered and folate receptor (FR) targeted triple-negative breast cancer (MDA-MB 231 cells) treatment. R-Pd NCs exhibited flower-shaped particles with an average size of <100 nm. FA-CS encapsulation concealed the flower shape of R-Pd NCs with a positive charge. The XRD spectrum confirmed the cubic crystalline structure of Pd. The FA conjugation on CS improved the cellular uptake of R-Pd NCs in MDA-MB 231 cells was confirmed by TEM. FA-CS-R-Pd NCs (+NIR) treatment was considerably inhibited the MDA-MB 231 cells proliferation evidenced by cell viability, fluorescent staining, and flow cytometry analysis. Further, in vitro hemolysis assay and in Ovo model confirmed the non-toxic nature of FA-CS-R-Pd-NCs with or without NIR radiation. Hence, this study concluded that FA-CS-R-Pd NCs can be applied for the treatment of drug-resistant breast cancer.

Nanostructure of Functional Larotaxel Liposomes Decorated with Guanine-Rich Quadruplex Nucleotide-Lipid Derivative for Treatment of Resistant Breast Cancer.

Breast cancer is the most common malignant disease in women all over the world and its chemotherapy outcome is restricted by multidrug resistance. Here, a nanostructure by functional larotaxel liposomes decorated with guanine-rich quadruplex nucleotide-lipid derivative for treatment of resistant breast cancer is developed. The studies are performed on the resistant breast cancer cells and the cancer-bearing mice. The nucleotide-lipid derivative (DSPE-PEG2000 -C6 -GT28nt) is synthesized by introducing a hydrophobic hexyl linkage between GT-28nt(containing 17 guanines and 11 thymidines) and DSPE-PEG2000 -NHS, and is incorporated on the functional larotaxel liposomes for specific binding with nucleolin receptor on the resistant cancer cells. The studies demonstrate that the liposomes had long circulatory effect, targeted capability, and significant anticancer efficacy in resistant cancer-bearing mice. The studies further reveal their action mechanism, consisting of blocking depolymerization of microtubules, arresting cell cycle, blocking JAK-STAT signaling pathway, and inhibiting activity of antiapoptotic proteins. In conclusion, the functional larotaxel liposomes can be used for effective treatment of drug-resistant breast cancer, and this study also offers a novel targeted nanomedicine based on nucleotide-lipid derivative.

Recent Advances in Therapeutic Peptides for Breast Cancer Treatment.

Breast cancer is a heterogeneous malignancy and is the second leading cause of mortality among women around the world. Increasing the resistance to anti-cancer drugs in breast cancer cells persuades researchers to search the novel therapeutic approaches for the treatment of this malignancy. Among the novel methods, therapeutic peptides that target and disrupt tumor cells have been of great interest. Therapeutic peptides are short amino acid monomer chains with high specificity to bind and modulate a protein interaction of interest. Several advantages of peptides, such as specific binding on tumor cells surface, low molecular weight, and low toxicity on normal cells, make the peptides appealing therapeutic agents against solid tumors, particularly breast cancer. Also, the National Institutes of Health (NIH) describes therapeutic peptides as a suitable candidate for the treatment of drug-resistant breast cancer. In this review, we attempt to review the different therapeutic peptides against breast cancer cells that can be used in the treatment and diagnosis of the malignancy. Meanwhile, we presented an overview of peptide vaccines that have been developed for the treatment of breast cancer.

Multifunctional Nanosystem for Targeted and Controlled Delivery of Multiple Chemotherapeutic Agents for the Treatment of Drug-Resistant Breast Cancer.

By targeting CD44 receptors, inhibiting multidrug resistance (MDR), controlling drug release, and synergistically inhibiting tumor growth, a multilayered nanosystem was developed to serve as a multifunctional platform for the treatment of drug-resistant breast cancers. The multilayer nanosystem is composed of a poly(lactic-co-glycolic acid) core, a liposome second layer, and a chitosan third layer. The chitosan-multilayered nanoparticles (Ch-MLNPs) can co-deliver three chemotherapeutic agents: doxorubicin (DOX), paclitaxel (PTX), and silybin. The three drugs are released from the multilayered NPs in a controlled and sequential manner upon internalization and localization in the cellular endosomes. The presence of a chitosan layer allows the nanosystem to target a well-characterized MDR breast cancer biomarker, the CD44s receptor. In vitro cytotoxicity study showed that the nanosystem loaded with triple drugs, DOX–PTX–silybin, resulted in better antitumor efficacy than the single-drug or dual-drug nano-formulations. Likely attributed to the MDR-inhibition effect of silybin, the co-delivered DOX and PTX exhibited a better synergistic effect on MDR breast cancer cells than on non-MDR breast cancer cells. The in vivo study also showed that the multilayered nanosystem promoted MDR inhibition and synergy between chemotherapeutic agents, leading to significant tumor reduction in a xenograft animal model. Ch-MLNPs reduced the tumor volume by fivefold compared to that of the control group without causing overt cytotoxicity.

Chitosan-alginate BSA-gel-capsules for local chemotherapy against drug-resistant breast cancer.

Background and objectPolyelectrolyte microcapsule is a promising candidate for multifunctional drug delivery system. However, the lack of reports about animal experiments have greatly slowed down their development for drug delivery. We engineered biodegradable chitosan–alginate polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule). Herein, we demonstrated their applicability for local chemotherapy, a means of treating local or regional malignancies by direct administration of anti-tumor agents to tumor sites.MethodDoxorubicin (DOX) was loaded in BSA-gel-capsules and DOX-resistant cell line (MCF-7/ADR cells) was employed for antitumor studies in vitro. The cytotoxicity, cellular uptake and distribution of DOX from BSA-gel-capsules were studied. Afterwards, MCF-7/ADR xenografts tumor model was established in nude mice. The in vivo antitumor efficacy of DOX-loaded BSA-gel-capsules by intratumor injection was then evaluated.ResultCompared with free DOX, more effective cytotoxicity against MCF-7/ADR cells after treatment with DOX-loaded BSA-gel-capsules was revealed, demonstrating the positive reversal effect on drug-resistance. Thereafter, the more cellular uptake and nucleus distribution of DOX from BSA-gel-capsules in MCF-7/ADR cells provided convincing explanation for the reversal effect. DOX-loaded BSA-gel-capsules displayed remarkably more antitumor efficacy than free DOX in MCF-7/ADR cell-xenografted mice. Finally, the high DOX accumulation and prolonged retention in tumor site after local administration of DOX-loaded BSA-gel-capsules was demonstrated, displaying the unique advantages of BSA-gel-capsules for local chemotherapy.ConclusionThese findings indicate that DOX-loaded BSA-gel-capsules should be considered a potential candidate for the treatment of drug-resistant breast cancer. This paper provides a feasibility for the local chemotherapy of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles.

Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer.

The combination of a chemotherapeutic drug with a chemosensitizer has emerged as a promising strategy for cancers showing multidrug resistance (MDR). Herein we describe the simultaneous targeted delivery of two drugs to tumor cells by using biotin-decorated poly(ethylene glycol)-b-poly(ε-caprolactone) nanoparticles encapsulating the chemotherapeutic drug doxorubicin and the chemosensitizer quercetin (BNDQ). Next, the potential ability of BNDQ to reverse MDR in vitro and in vivo was investigated. Studies demonstrated that BNDQ was more effectively taken up with less efflux by doxorubicin-resistant MCF-7 breast cancer cells (MCF-7/ADR cells) than by the cells treated with the free drugs, single-drug–loaded nanoparticles, or non-biotin–decorated nanoparticles. BNDQ exhibited clear inhibition of both the activity and expression of P-glycoprotein in MCF-7/ADR cells. More importantly, it caused a significant reduction in doxorubicin resistance in MCF-7/ADR breast cancer cells both in vitro and in vivo, among all the groups. Overall, this study suggests that BNDQ has a potential role in the treatment of drug-resistant breast cancer.

Efficacy and mechanism of a compound epirubicin plus quinine injection for the treatment of drug-resistant breast cancer

Efficacy and mechanism of a compound epirubicin plus quinine injection for the treatment of drug-resistant breast cancer

Dopamine enhances the response of sunitinib in the treatment of drug-resistant breast cancer: Involvement of eradicating cancer stem-like cells

Growing evidence suggests that the efficacy of sunitinib in breast cancer may be limited by increasing the population of cancer stem-like cells (CSCs). Hence the concurrent use of CSCs-targeting agents is required. Previous results indicated that dopamine receptor (DR) may serve as a potential therapeutic target of anti-CSCs therapies. This study focused on evaluating the effect of dopamine (an agonist of DR) on the enhancement of sunitinib's efficacy in the treatment of drug-resistant breast cancer, investigating the involved activation type of DR pathway and exploring the underlying anti-CSCs mechanisms. MCF-7 cells, MCF-7/Adr cells and breast cancer stem-like cells (BCSCs) were used for in vitro study. Moreover, MCF-7/Adr cells and BCSCs were selected as drug-resistant cell lines and further used for in vivo development of the xenograft animal models. Our results showed that dopamine greatly synergized the inhibitory effect of sunitinib in the drug-resistant cells and strikingly enhanced the response of sunitinib in both xenograft models. It was found that dopamine significantly down-regulated the expression of BCSCs markers (CD44+/CD24−) in vitro and in vivo. In addition, dopamine remarkably induced the apoptosis of BCSCs, markedly inhibited the Wnt signaling pathway and activated the apoptotic associated signals. The activation of dopamine receptor D1 (D1DR) pathway may be involved in the underlying mechanism as D1DR's antagonist SCH23390 completely reversed the combined effects. In conclusion, dopamine may eradicate CSCs and it significantly enhances the response of sunitinib in the treatment of drug-resistant breast cancer.

Role of miR-155 in drug resistance of breast cancer.

MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expressions at posttranscriptional level. Growing evidence points to their significant role in the acquisition of drug resistance in cancers. Studies show that miRNAs are often aberrantly expressed in human cancer cells which are associated with tumorigenesis, metastasis, invasiveness, and drug resistance. Breast cancer is the leading cause of cancer-induced death in women. Over the last decades, increasing attention has been paid to the effects of miRNAs on the development of breast cancer drug resistance. Among them, miR-155 takes part in a sequence of bioprocesses that contribute to the development of such drug resistance, including repression of FOXO3a, enhancement of epithelial-to-mesenchymal transition (EMT) and mitogen-activated protein kinase (MAPK) signaling, reduction of RhoA, and affecting the length of telomeres. In this review, we discuss the role of miR-155 in the acquisition of breast cancer drug resistance. This will provide a new way in antiresistance treatment of drug-resistant breast cancer.

MPEG-b-PCL/TPGS mixed micelles for delivery of resveratrol in overcoming resistant breast cancer

Objective: Drug resistance remains a major challenge for effective breast cancer chemotherapy. Resveratrol (Res) is a promising candidate for overcoming cancer chemoresistance, but it has low bioavailability due to poor absorption, and ready metabolism limits its application. This study aims to develop a Res-loaded mixed micelle system to be effective on drug resistance of breast cancer cells.Methods: A mixed micelle system made of methoxy poly (ethylene glycol)-b-polycaprolactone (mPEG-PCL) and d-α-Tocopherol polyethylene glycol succinate was prepared and Res was encapsulated to form Res-loaded mixed micelles. Furthermore, the antitumor activity against doxorubicin (Dox)-resistant breast cancer MCF-7/ADR cells was studied and the possible mechanism was elucidated.Results: The mixed micellar formulation increased drug uptake efficiency of Res by Dox-resistant breast cancer MCF-7/ADR cells, and induced higher rates of apoptotic cell death, as assessed by the accumulation of Sub G1 phases of cell cycle, nucleus staining and Annexin-FITC/propidium iodide assay. Moreover, Res-loaded mixed micelles also markedly enhanced Dox-induced cytotoxicity in MCF-7/ADR cells and increased the cellular accumulation of Dox by downregulating the expression of P-glycoprotein (P-gp) and inhibiting the activity thereof.Conclusion: The cumulative evidence indicates that Res-loaded mixed micelles hold significant promise for the treatment of drug-resistant breast cancer.

Abstract P4-07-10: MicroRNAs as biomarkers and therapeutic adjuvants for the prognosis and treatment of drug-resistant breast cancers

Abstract Intrinsic and acquired resistance to antineoplastic agents continues to be a major clinical impediment to successful treatment of cancer in general, and breast cancer in particular. For example, about 40% of ER-positive metastatic breast tumors fail to respond to tamoxifen therapy, and of those that initially respond many will eventually develop resistance. Similarly, taxanes used as a first-line chemotherapy agent will have a response rate of 50%, which comes down to 20–30% in second- or third-line chemotherapy; nearly half of the treated subjects do not respond to it and suffer side effects. These facts underscore the importance of understanding the mechanism of resistance, which is crucial for the optimal systemic therapy of breast cancer. Unfortunately, in spite of extensive inquiry in this field, little is known about the key molecules/signaling pathways that regulate this phenomenon. Recently, we have discovered that small non-coding RNAs, i.e. microRNA (miRNAs), may play a critical role in mediating drug resistance in breast cancers. We have identified miRNAs that are differentially expressed between drug-resistant and sensitive breast cancer cells. Specifically, we have combined a high-throughput screening platform with a library of chemically synthesized inhibitors for all known human miRNAs and identified specific miRNA that selectively sensitize/de-sensitize drug-resistant breast cancer cells to either tamoxifen or trastuzumab (herceptin), drugs that are commonly used as a first line treatment for ER-positive and Her2-positive breast cancers, respectively. We identified 10 and 12 miRNA inhibitors that sensitized resistant cells to tamoxifen and trastuzumab, respectively. Interestingly, expression of cognate miRNA/s that sensitize resistant tumors to drug-induced cell death in our screen was found to be lower in relapsed (drug-resistant) metastatic breast cancer patients compared to normal matched control. In addition to tumor tissues, the levels of sensitizer miRNA/s in the blood sera of relapsed metastatic breast cancer patients was found to be dramatically lower than that of normal healthy individual. These findings are significant as it suggests that miRNAs can be efficiently detected in blood serum and therefore, can be used as a potential biomarker for predicting treatment outcomes. In addition, miRNAs may provide novel therapeutic tools for the treatment of drug-resistant breast cancers. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-07-10.

Tetraiodothyroacetic Acid-Conjugated PLGA Nanoparticles: A Nanomedicine Approach to Treat Drug-Resistant Breast Cancer

The aim was to evaluate tetraiodothyroacetic acid (tetrac), a thyroid hormone analog of L-thyroxin, conjugated to poly(lactic-co-glycolic acid) nanoparticles (T-PLGA-NPs) both in vitro and in vivo for the treatment of drug-resistant breast cancer. The uptake of tetrac and T-PLGA-NPs in doxorubicin-resistant MCF7 (MCF7-Dx) cells was evaluated using confocal microscopy. Cell proliferation assays and a chick chorioallantoic membrane model of FGF2-induced angiogenesis were used to evaluate the anticancer effects of T-PLGA-NPs. In vivo efficacy was examined in a MCF7-Dx orthotopic tumor BALBc nude mouse model. T-PLGA-NPs were restricted from entering into the cell nucleus, and T-PLGA-NPs inhibited angiogenesis by 100% compared with 60% by free tetrac. T-PLGA-NPs enhanced inhibition of tumor-cell proliferation at a low-dose equivalent of free tetrac. In vivo treatment with either tetrac or T-PLGA-NPs resulted in a three- to five-fold inhibition of tumor weight. T-PLGA-NPs have high potential as anticancer agents, with possible applications in the treatment of drug-resistant cancer.

Abstract P5-10-14: MicroRNAs as biomarkers and therapeutic adjuvants for the prognosis and treatment of drug-resistant breast cancers

Abstract Intrinsic and acquired resistance to antineoplastic agents continues to be a major clinical impediment to successful treatment of cancer in general, and breast cancer in particular. For example, about 40% of ER-positive breast tumors fail to respond to tamoxifen therapy, and of those that initially respond many will eventually develop resistance. Similarly, taxanes used as a first-line chemotherapy agent will have a response rate of 50%, which comes down to 20–30% in second- or third-line chemotherapy; nearly half of the treated subjects do not respond to it and suffer side effects. These facts underscore the importance of understanding the mechanism of resistance, which is crucial for better management of breast cancer. Unfortunately, in spite of extensive inquiry in this field, little is known about the key molecules/signaling pathways that regulate this phenomenon. Recently, we have discovered that small non-coding RNAs, i.e. microRNA (miRNAs), may play a critical role in mediating drug resistance in breast cancers. We have identified miRNAs that are differentially expressed between chemoresistant and sensitive breast cancer cells. Specifically, we have combined a high-throughput screening platform with a library of chemically synthesized inhibitors for all known human miRNAs and identified specific miRNA that selectively sensitize/de-sensitize drug-resistant breast cancer cells to either tamoxifen or trastuzumab (herceptin), drugs that are commonly used as a first line treatment for ER-positive and Her2-positive breast cancers, respectively. Interestingly, we identified 10 and 12 miRNA inhibitors that sensitized resistant cells to tamoxifen and trastuzumab, respectively. Interestingly, expression of cognate miRNA/s that sensitize resistant tumors to drug-induced cell death in our screen was found to be lower in relapsed (drug resistant) metastatic breast cancer patients compared to normal matched control. In addition to tumor tissues, the levels of sensitizer miRNA/s in the blood sera of relapsed metastatic breast cancer patients was found to be dramatically lower than that of normal healthy individual. These findings are significant as it suggests that miRNAs can be efficiently detected in blood serum and therefore, can be used as a potential biomarker for predicting treatment outcomes. In addition, miRNAs may provide novel therapeutic tools for the treatment of drug-resistant breast cancers. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-10-14.

Novel Drug Target May Assist Treatment of Drug-Resistant Breast Cancer

Novel Drug Target May Assist Treatment of Drug-Resistant Breast Cancer

Enhanced killing of chemo-resistant breast cancer cells via controlled aggravation of ER stress

Moderate activity of the endoplasmic reticulum (ER) stress response system exerts anti-apoptotic function and supports tumor cell survival and chemoresistance, whereas its more severe aggravation may exceed the protective capacity of this system and turn on its pro-apoptotic module. In this study, we investigated whether the combination of two pharmacologic agents with known ability to trigger ER stress via different mechanisms would synergize and lead to enhanced tumor cell death. We combined the HIV protease inhibitor nelfinavir (Viracept ®) and the cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex ®) and investigated their combined effect on ER stress and on the viability of breast cancer cells. We found that this drug combination aggravated ER stress and caused pronounced toxicity in human breast cancer cell lines, inclusive of variants that were highly resistant to other therapeutic treatments, such as doxorubicin, paclitaxel, or trastuzumab. The anti-tumor effects of celecoxib were mimicked at increased potency by its non-coxib analog, 2,5-dimethyl-celecoxib (DMC), but were substantially weaker in the case of unmethylated-celecoxib (UMC), a derivative with superior COX-2 inhibitory efficacy. We conclude that the anti-tumor effects of nelfinavir can be enhanced by celecoxib analogs in a COX-2 independent fashion via the aggravation of ER stress, and such drug combinations should be considered as a beneficial adjunct to the treatment of drug-resistant breast cancers.

Advances of clinical treatment of drug-resistant advanced breast cancer

In the current clinical trials,observed treatment on recrudescent and metastatic breast cancer which can be anthracycline-resistant and taxane-resistant with Ixabepilone、Larotaxel and their combination;and treating climacteric-positive and tamoxifen-resistant advanced breast cancer with steroid sulfatase inhibitor STX64 or combination of exemestane and celecoxib;Treating chemotherapy-refractory HER2-positive metastatic breast cancer with lapatinib and pemetrexed as well as their combination.Results have demonstrated superior efficacy and safety,and some of which are worthy of further observation. Key words: Breast neoplasms; Drug therapy