Therapeutic Strategy For Breast Cancer Research Articles

Simultaneous inhibition of breast cancer and its liver and lung metastasis by blocking inflammatory feed-forward loops

Inflammatory feed-forward loops including the steps of “inflammatory cell recruitment”, “inflammatory signaling pathway activation” and “inflammatory factor production” are essential in the development of breast cancer and its metastasis. Herein, a doxorubicin-loaded micellar low-molecular-weight-heparin-astaxanthin nanoparticle (LMWH-AST/DOX, LA/DOX NP) was developed. The hydrophilic LMWH could decrease the recruitment of neutrophils in liver and myeloid-derived suppressor cells (MDSCs) in lung and tumor through P-selectin blockage. The hydrophobic AST could inhibit nuclear factor-κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. Therefore, LA/DOX NPs could block these loops and suppress the liver metastasis by inhibiting the formation of neutrophil extracellular traps (NETs), inhibit the lung metastasis and alleviate the inflammatory and immunosuppressive microenvironment in tumor. This is the first functional nanoparticle reported to shut down inflammatory feed-forward loops and the formation of NETs, which provides a promising therapeutic strategy for breast cancer and its liver and lung metastasis.

Cytotoxic Effects of Hellebrigenin and Arenobufagin Against Human Breast Cancer Cells.

Development of new therapeutic strategies for breast cancer is urgently needed due to the sustained emergence of drug resistance, tumor recurrence and metastasis. To gain a novel insight into therapeutic approaches to fight against breast cancer, the cytocidal effects of hellebrigenin (Helle) and arenobufagin (Areno) were investigated in human estrogen receptor (ER)-positive breast cancer cell line MCF-7 and triple-negative breast cancer cell line MDA-MB-231. Helle exhibited more potent cytotoxicity than Areno in both cancer cells, and MCF-7 cells were more susceptible to both drugs in comparison with MDA-MB-231 cells. Apoptotic-like morphological characteristics, along with the downregulation of the expression level of Bcl-2 and Bcl-xL and the upregulation of the expression level of Bad, were observed in Helle-treated MCF-7 cells. Helle also caused the activation of caspase-8, caspase-9, along with the cleavage of poly(ADP-ribose) polymerase in MCF-7 cells. Helle-mediated necrosis-like phenotype, as evidenced by the increased propidium iodide (PI)-positive cells was further observed. G2/M cell cycle arrest was also induced by Helle in the cells. Upregulation of the expression level of p21 and downregulation of the expression level of cyclin D1, cyclin E1, cdc25C and survivin were observed in MCF-7 cells treated with Helle and occurred in parallel with G2/M arrest. Autophagy was triggered in MCF-7 cells and the addition of wortmannin or 3-MA, two well-known autophagy inhibitors, slightly but significantly rescued the cells. Furthermore, similar alterations of some key molecules associated with the aforementioned biological phenomena were observed in MDA-MB-231 cells. Intriguingly, the numbers of PI-positive cells in Helle-treated MCF-7 cells were significantly reduced by wortmannin and 3-MA, respectively. In addition, Helle-triggered G2/M arrest was significantly corrected by wortmannin, suggesting autophagy induction contributed to Helle-induced cytotoxicity of breast cancer cells by modulating necrosis and cell cycle arrest. Collectively, our results suggested potential usefulness of both Helle and Areno in developing therapeutic strategies to treat patients with different types of breast cancer, especially ER-positive breast cancer.

Expression of HLA-DR in Cytotoxic T Lymphocytes: A Validated Predictive Biomarker and a Potential Therapeutic Strategy in Breast Cancer.

Simple SummaryMore than 50% of breast cancer (BC) patients selected for neoadjuvant chemotherapy (NACT) are subjected to at least a 6-month regimen of this treatment without a clear benefit, probably delaying more effective therapeutic strategies and being exposed to potential treatment-associated toxicity. Thus, it is urgent to implement reliable predictive biomarkers, as well as novel treatments for NACT non-responder patients. This study validates that the HLA-DR level in cytotoxic T lymphocytes (CTLs) is an independent and robust predictive factor of BC patients’ response to NACT, as previously proposed. Hence, a predictive probability model of response was developed as a new tool to improve treatment decisions. HLA-DR level in CTLs also have a general prognostic value, which might be relevant for long-term BC management. In addition, our results suggest that increasing the expression of HLA-DR in CTLs of non-responders could be a promising therapeutic strategy to ameliorate BC response to NACT.Neoadjuvant chemotherapy (NACT) is common in breast cancer (BC) treatment, though more than half of the patients lack an effective response. Therefore, new predictive biomarkers and alternative therapies are crucial. Previously, we proposed HLA-DR-expressing cytotoxic T lymphocytes (CTLs) as a potential biomarker of the response to NACT. To validate this observation and further investigate these cells, 202 BC patients were enrolled. Flow cytometry analyses were performed in 61 biopsies and 41 blood samples pre-NACT and 100 non-NACT tumor samples. All the patients were followed up for 34 months. Blood-isolated immune cells were cultured with BC cell lines in a 3D system. We confirmed that HLA-DR level in CTLs is a highly sensitive, specific, and independent biomarker to predict response to NACT and developed a predictive probability model. This biomarker was also associated with progression-free survival, regardless of the treatment. The clinical observations are substantiated by the anti-tumor properties of HLA-DR-expressing CTLs. Intriguingly, HLA-DR level in CTLs can be modulated ex vivo, boosting their capacity to kill tumor cells synergistically with doxorubicin. Thus, HLA-DR expression in CTLs is a validated tool to select patients that will actually benefit from NACT, and its stimulation might be a novel therapeutic approach for BC.

Exosomes of Mesenchymal Stem Cells as a Proper Vehicle for Transfecting miR-145 into the Breast Cancer Cell Line and Its Effect on Metastasis.

Background Despite recent advances in scientific knowledge and clinical practice, management, and treatment of breast cancer, as one of the leading causes of female mortality, breast cancer remains a major burden. Recently, methods employing stem cells and their derivatives, i.e., exosomes, in gene-based therapies hold great promise. Since these natural nanovesicles are able to transmit crucial cellular information which can be engineered to have robust delivery and targeting capacity, they are considered one of the modes of intercellular communication. miR-145, one of the downregulated microRNAs (miRNAs) in various cancers, can regulate tumor cell invasion, metastasis, apoptosis, and proliferation and stem cell differentiation. Objectives The aim of this study was to investigate the role of exosomes secreted from adipose tissue-derived mesenchymal stem cells (MSCs) for miR-145 transfection into breast cancer cells in order to weaken their expansion and metastasis. Methods Here, we exploited the exosomes from adipose tissue-derived mesenchymal stem cells (MSC-Exo) to deliver miR-145 in the T-47D breast cancer cell line. Lentiviral vectors of miR-145-pLenti-III-enhanced green fluorescent protein (eGFP) and empty pLenti-III-eGFP as the backbone were used to transfect MSCs and T-47D cells. In order to find the efficiency of exosomes as a delivery vehicle, the expression level of some miR-145 target genes, including Rho-Associated Coiled-Coil Containing Protein Kinase 1 (ROCK1), Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2), Matrix Metalloproteinase 9 (MMP9), and Tumor Protein p53 (TP53), was compared in all treatment groups (T-47D cells treated by miR-145-transfected MSCs and their derivatives or their backbone) and control group (untransfected T-47D cells) using real-time PCR. Results The obtained data represented the inhibitory effect of miR-145 on apoptosis induction and metastasis in both direct miR-treated groups. However, exosome-mediated delivery caused an improved anticancer property of miR-145. Conclusion Restoration of miR-145 using MSC-Exo can be considered a potential novel therapeutic strategy in breast cancer in the future.

A Novel Prognostic Biomarker of Luminal Breast Cancer: High CD39 Expression Is Related to Poor Survival.

BackgroundCD39 is one of the functional surface markers for T regulatory cells, the prognostic role and immune-related effects of CD39 in luminal breast cancer (BC) patients has not been evaluated yet. The aim of the current study was to explore the association between CD39 expression and clinic pathological characteristics and the prognosis in luminal BC patients.MethodsClinical information and RNA-sequencing (RNA-Seq) expression data were extracted from The Cancer Genome Atlas (TCGA). Patients were divided into a high or low CD39 expression group by the optimal cutoff value (4.18) identified from the receiver operating characteristic curve analysis. The relationships between CD39 expression and clinic pathological features were evaluated by the corresponding statistical tests. Survival analyses were applied to evaluate the overall survival between the high and low CD39 expression groups in luminal BC. Furthermore, Gene Expression Omnibus datasets were used for external data validation. Gene set enrichment analysis (GSEA) was also performed, and CIBERSORT was used to analyze the immune cell populations.ResultsAnalysis of 439 cases of tumor data showed that CD39 was overexpressed in luminal BC. The multivariable analysis suggested that CD39 expression was an independent prognostic factor for luminal BC patients. GSEA suggested that CD39 might play an important role in luminal BC progression through immune regulation. Analysis of immune cell patterns revealed high CD39 expression correlated to a higher proportion of CD8+ T cells and M2 macrophages.ConclusionThis study demonstrates that CD39 expression correlates with the prognosis of luminal BC through TCGA database mining. Further studies are warranted further to elucidate this potential novel therapeutic strategy for BC.

The extracellular-regulated protein kinase 5 (ERK5) enhances metastatic burden in triple-negative breast cancer through focal adhesion protein kinase (FAK)-mediated regulation of cell adhesion

There is overwhelming clinical evidence that the extracellular-regulated protein kinase 5 (ERK5) is significantly dysregulated in human breast cancer. However, there is no definite understanding of the requirement of ERK5 in tumor growth and metastasis due to very limited characterization of the pathway in disease models. In this study, we report that a high level of ERK5 is a predictive marker of metastatic breast cancer. Mechanistically, our in vitro data revealed that ERK5 was critical for maintaining the invasive capability of triple-negative breast cancer (TNBC) cells through focal adhesion protein kinase (FAK) activation. Specifically, we found that phosphorylation of FAK at Tyr397 was controlled by a kinase-independent function of ERK5. Accordingly, silencing ERK5 in mammary tumor grafts impaired FAK phosphorylation at Tyr397 and suppressed TNBC cell metastasis to the lung without preventing tumor growth. Collectively, these results establish a functional relationship between ERK5 and FAK signaling in promoting malignancy. Thus, targeting the oncogenic ERK5-FAK axis represents a promising therapeutic strategy for breast cancer exhibiting aggressive clinical behavior.

FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors at the crossroads: the combinational therapeutic strategies in breast cancer—a narrative review

Cyclin-dependent kinase 4 and 6 inhibitors at the crossroads: the combinational therapeutic strategies in breast cancer—a narrative review

Dihydroartemisinin induces pyroptosis by promoting the AIM2/caspase-3/DFNA5 axis in breast cancer cells

BackgroundBreast cancer is a complex disease. Recent research has examined the anticancer effects of dihydroartemisinin (DHA) on breast cancer. However, the molecular mechanism of the antitumour effect of DHA is unclear. MethodsMCF-7 and MDA-MB-231 cell lines were used for in vitro research. BALB/c nude mice were used to establish breast cancer xenografts. The mRNA and protein levels were analysed by qRT-PCR and western blotting, respectively. Flow cytometry was performed to examine cell apoptosis. ELISA kits were used to evaluate the production of interleukin-1β (IL-1β) and IL-18. LDH and ATP release were individually measured with the corresponding kits. A colony formation assay was used to examine the proliferation of breast cancer cells. ResultsDHA inhibited proliferation and induced pyroptosis in breast cancer cells. Mechanistically, DHA activated the expression of absent in melanoma 2 (AIM2), caspase-3 and gasdermin E (DFNA5). In addition, AIM2 promoted DFNA5 expression by activating caspase-3. Knockdown of AIM2 and DFNA5 significantly enhanced breast cancer cell resistance to DHA. In vivo experiments showed that the tumorigenicity of breast cancer cells was significantly suppressed by DHA. Moreover, the AIM2/caspase-3/DFNA5 axis was activated by DHA and then induced pyroptosis. ConclusionsOur findings indicate that DHA inhibits tumorigenesis by inducing pyroptosis in breast cancer cells, highlighting a promising therapeutic strategy for breast cancer.

Melatonin and vitamin D: complementary therapeutic strategies for breast cancer.

Melatonin and vitamin D: complementary therapeutic strategies for breast cancer.

Identification of FPR3 as a Unique Biomarker for Targeted Therapy in the Immune Microenvironment of Breast Cancer.

Although research into immunotherapy is growing, its use in the treatment of breast cancer remains limited. Thus, identification and evaluation of prognostic biomarkers of tissue microenvironments will reveal new immune-based therapeutic strategies for breast cancer. Using an in silico bioinformatic approach, we investigated the tumor microenvironmental and genetic factors related to breast cancer. We calculated the Immune score, Stromal score, Estimate score, Tumor purity, TMB (Tumor mutation burden), and MATH (Mutant-allele tumor heterogeneity) of Breast cancer patients from the Cancer Genome Atlas (TCGA) using the ESTIMATE algorithm and Maftools. Significant correlations between Immune/Stromal scores with breast cancer subtypes and tumor stages were established. Importantly, we found that the Immune score, but not the Stromal score, was significantly related to the patient's prognosis. Weighted correlation network analysis (WGCNA) identified a pattern of gene function associated with Immune score, and that almost all of these genes (388 genes) are significantly upregulated in the higher Immune score group. Protein-protein interaction (PPI) network analysis revealed the enrichment of immune checkpoint genes, predicting a good prognosis for breast cancer. Among all the upregulated genes, FPR3, a G protein-coupled receptor essential for neutrophil activation, is the sole factor that predicts poor prognosis. Gene set enrichment analysis analysis showed FRP3 upregulation synergizes with the activation of many pathways involved in carcinogenesis. In summary, this study identified FPR3 as a key immune-related biomarker predicting a poor prognosis for breast cancer, revealing it as a promising intervention target for immunotherapy.

Mitochondria-Associated Endoplasmic Reticulum Membranes in Breast Cancer.

Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.

Ras Signaling in Breast Cancer.

Ras proteins mediate extracellular and cytoplasmic signaling networks via receptor tyrosine kinase. The Ras pathway induces activation of signaling molecules involved in cell proliferation and growth, cell survival and apoptosis, metabolism, and motility. Although Ras mutations in breast cancer are not frequently reported, hyperactivation of Ras signaling plays an important role in breast cancer growth and progression. Oncogenic Ras activation occurs via loss of Ras GTPase-activating proteins, overexpression of growth factor receptor, and stimulation by various cytokines. Effective control of oncogenic Ras is one of the therapeutic strategies in breast cancer. The mechanisms of intracellular localization, activation, and signaling pathway of Ras in cancer have been used to develop therapeutic candidates. Recent studies have reported an effective therapy for breast cancer by inhibition of enzymes involved in the posttranslational modification of Ras, such as farnesyltransferase and geranylgeranyltransferase 1, and anti-cancer therapies targeting the epidermal growth factor receptor (EGFR). Emerging targets involved in EGF-mediated Ras activity in breast cancer have shed new insight into Ras activation in breast cancer progression. These alternative mechanisms for Ras signaling pathway may suggest novel therapeutic approaches for targeting Ras in breast cancer. In spite of the difficulties in targeting Ras protein, important discoveries highlight the direct inhibition of Ras activity. Further studies may elucidate the effects of targeting Ras protein and the clinical relevance thereof.

Echinacoside Suppresses the Progression of Breast Cancer by Downregulating the Expression of miR-4306 and miR-4508.

The main treatment of breast cancer includes surgical resection, radiotherapy, chemotherapy, endocrine therapy, and molecular targeted therapy, but the outcomes remain unsatisfactory. Previous studies demonstrated that echinacoside, microRNA (miRNA/miR)-4306 and miR-4508 were associated with lymph node metastasis, chemoresistance and self-renewal capability in breast cancer, but in-depth studies on the underlying mechanism of their anticancer effects have not been performed to date. In order to identify the role of miR-4306 and miR-4508, and the mechanism of the antitumor effect of echinacoside in breast cancer, the present study first examined the expression of miR-4306 and miR-4508 in breast cancer tissues to examine their possible role in the development of breast cancer, then evaluated the effect of echinacoside on the expression of miR-4306 and miR-4508 on the viability, apoptosis, cell cycle, migration, and invasion abilities of breast cancer cells to explore the anti-cancer effect of echinacoside and the involvement of miR-4306 and miR-4508. Finally, the breast cancer cells and mice bearing breast cancer xenografts were treated with echinacoside and inhibitors of miR-4508 or miR-4306 to confirm their role on the anticancer effect of echinacoside. The results showed that miR-4306 and miR-4508 were decreased in breast cancer tissues and cells. Echinacoside inhibited cell proliferation, invasion and migration, and promoted the apoptosis of breast cancer cells by downregulating the expression of miR-4306 and miR-4508. In conclusion, this is the first study to show the association between echinacoside and miRNAs in cancer. The present study elucidates an underlying molecular mechanism of the antitumor effect of echinacoside on breast cancer, and thus may contribute to preventive and therapeutic strategies for breast cancer.

MiR-4443 promotes migration and invasion of breast cancer cells by inhibiting PEBP1 expression

To investigate the effect of miR-4443 expression on migration and invasion of breast cancer. We examined the expression of miR-4443 in breast carcinoma in situ and paired adjacent tissues from 3 breast cancer patients with high-throughput sequencing and verified the results using TCGA database. We also detected miR-4443 expressions using real-time quantitative PCR (RT-qPCR) in low invasive and highly invasive breast cancer cells (MCF-7 and MDA-MB-231 cells, respectively). The changes in apoptosis, migration and invasion of MCF-7 and MDA-MB-231 cells after transfection with miR-4443 mimics, mimics-NC, miR-4443 inhibitor or inhibitor-NC were analyzed using flow cytometry, wound healing assay and Transwell invasion assay. The target gene of miR-4443 was predicted by bioinformatics software and validated by a dual luciferase reporter gene system. RT-qPCR and Western blotting were performed to detect the expression of recombinant human phosphatidyl ethanolamine binding protein 1 (PEBP1) in the transfected cells. The expression of miR-4443 was significantly higher in the breast cancer tissues than in the adjacent tissues (P < 0.01), and was significantly up-regulated in MDA-MB-231 cells as compared with MCF-7 cells (P < 0.01). Transfection with miR-4443 mimics or inhibitors did not obviously affect apoptosis rate of the breast cancer cells (P>0.05), but significantly enhanced or weakened the migration and invasion abilities of the cells, respectively (P < 0.01). Bioinformatic analysis identified PEBP1 as the target gene of miR-4443 with a close correlation with metastasis of breast cancer (P < 0.01), and the result was confirmed by double luciferase reporter gene assay. The mRNA and protein expression of PEBP1 were significantly lower in MDA-MB-231 cells than in MCF-7 cells (P < 0.01), and miR-4443 over-expression or knockdown significantly down-regulated or up-regulated PEBP1 expressions in the cells, respectively (P < 0.01). MiR-4443 promotes the migration and invasion of breast cancer cells by inhibiting the expression of PEBP1, suggesting the possibility of suppressing miR-4443 expression as a potential therapeutic strategy for breast cancer.

Narrative review of the application of radiotherapy in nipple-areola-complex–sparing mastectomy

: In the treatment of breast cancer, the effective removal of the tumor was once the sole aim of surgery. However, the goals of breast cancer surgery have shifted, with considerable emphasis now placed on improving the appearance and function of the breast while leaving the curative effect unaffected or even improved. Nipple-areola-complex-sparing mastectomy (NSM) facilitates breast reconstruction by preserving the skin and nipple-areola complex (NAC) of the breast. In recent years, this approach has become increasingly popular; however, it still carries a high risk of local recurrence in the NAC. Therefore, for patients who NSM, adjuvant radiotherapy (RT) is recommended. Although adjuvant radiation therapy is the standard of care for breast cancer treatment following lumpectomy, the application of RT after NSM is controversial. Previous studies on the roles of pre-, intra-, and/or postoperative RT combined with NSM have produced inconsistent results. Conventional preoperative or postoperative RT for breast cancer can cause contracture deformation of the implanted prosthesis. The emergence of intraoperative RT technology has further optimized radiotherapy-assisted NSM combined with breast reconstruction as a therapeutic strategy for breast cancer. The main complications of this treatment include fat necrosis, radiation fibrosis, and prosthesis contracture. Based on the selection of suitable patients, adjuvant RT is applied in combination with NSM according to the risk of local disease recurrence. In this article, we review the application of RT in NSM and compare studies on NSM combined with pre-, intra-, and/or postoperative RT.

Uncovering temperature-dependent extracellular vesicle secretion in breast cancer.

In all living things, temperature is a key factor to maintain function and survive. Animals and plants need to adapt temperature change with optimizing their behaviour and growth by sensing temperature. Similarly, tumour cells must adapt continuously to fluctuations in external conditions including temperature. To find a better environment, cancer cells promote growth and metastasis, which contributes to tumour malignancy. Pathological studies in breast cancer have implied that temperature is associated with disease progression. However, no clear mechanisms have emerged for how thermal changes affect tumour cells and their gene regulation in tumour development and malignancy. Here we discovered the temperature‐dependent extracellular vesicle (EV) secretion in breast cancer. Cancer cell growth and EV secretion increased in a temperature‐dependent manner, which indicated that temperatures were associated with poor prognosis in breast cancer patients. We also found that low‐density lipoprotein receptor (LDLR), a responsible gene for temperature‐dependent EV secretion, was upregulated with the increase in temperature. Consistent with our results, LDLR gene has been characterized and identified as a key factor for malignancy in a wide range of cancers. Our findings shed new light on tumour aggressiveness and therapeutic strategies for breast cancer, especially regarding EV formation and secretion, thus providing a new relationship between cancer and EV biology in the light of temperature.

PGC-1α activates SIRT3 to modulate cell proliferation and glycolytic metabolism in breast cancer.

Breast cancer is the leading cause of death among women. PGC-1α plays an important role in the regulation of metabolic reprogramming in cancer cells. SIRT3 has significant implications for tumor growth. In this study, we explored the roles of PGC-1α and SIRT3 in cell proliferation and mitochondrial energy metabolism alterations in breast cancer cells. The expression patterns of PGC-1α and SIRT3 were examined using qRT-PCR and western blotting analysis. MCF-7 and MDA-MB-231 cells were infected with adenovirus to overexpress or knock down the expression of PGC-1α and SIRT3. Cell viability and apoptosis were analyzed by CCK-8 and flow cytometry, respectively. Hexokinase 2, pyruvate kinase activities, as well as NAD+/NADH ratio and ATP concentration, were assessed by commercial kits. Glucose consumption was measured using the glucose oxidase method and lactic acid concentration was detected by lactate dehydrogenase kit. Expression levels of PGC-1 and SIRT3 were much lower in breast cancer patients, compared with the normal controls. Overexpression of PGC-1α or SIRT3 both significantly promoted the apoptosis and inhibited the proliferation in MCF-7 and MDA-MB-231 cells. Additionally, PGC-1α or SIRT3 also induced the inhibition of glycolysis metabolism. Moreover, the expression of SIRT3 was positively regulated by PGC-1α. Silencing SIRT3 partly reversed the negative effects of PGC-1α on glycolytic metabolism. These findings demonstrated that PGC-1α/SIRT3 regulated cell proliferation and apoptosis of breast cancer through altering glycolysis, which may provide novel therapeutic strategies for breast cancer.

Long noncoding RNA MEG3 suppresses cell proliferation, migration and invasion, induces apoptosis and paclitaxel-resistance via miR-4513/PBLD axis in breast cancer cells

ABSTRACT Breast cancer remains a general-threat event in the health of women. Currently, increasing records indicate that long non-coding RNA maternally expressed 3 (MEG3) plays a central role in breast cancer. The current research focused on the function of MEG3 in paclitaxel (PTX)-resistance and human breast cancer growth. Levels of MEG3, microRNA (miR)-4513, and phenazine biosynthesis-like domain-containing protein (PBLD) were evaluated using quantitative real-time polymerase chain reaction (qRT-PCR) or western blot assays. 3-(4.5-dimethylghiazol-2-yl)-2,5-diphenyltetrazolium Bromide (MTT) assay was performed to examine the IC50 of PTX and cell proliferation in breast cancer cells. In addition, cell apoptosis was determined utilizing flow cytometry. Transwell was conducted to assay cell migration and invasion in MCF-7 and MDA-MB-231 cells. The interaction between miR-4513 and MEG3 or PBLD was expounded via dual-luciferase reporter assay. Levels of MEG3 and PBLD were decreased, but miR-4513 level was triggered in breast cancer tissues and cell lines. Overexpression of MEG3 could reinforce cell apoptosis, impede proliferation, migration, invasion, and the IC50 of PTX in breast cancer cells. Moreover, the impact of miR-4513 inhibitor on cell progression and PTX-resistance was overturned by MEG3 deficiency. Interestingly, miR-4513 mimic could abolish the role of PBLD upregulation in cell behaviors and PTX-resistance in MCF-7 and MDA-MB-231 cells. Finally, the expression of PBLD was co-modulated by miR-4513 and MEG3 in vitro. MEG3/miR-4513/PBLD axis modulated PTX-resistance and the development of breast cancer cells, which might provide a promising therapeutic strategy for breast cancer.

Combined treatment with auranofin and trametinib induces synergistic apoptosis in breast cancer cells

ABSTRACT Auranofin is a gold complex used as an anti-rheumatic agent and may act as a potent anticancer drug against breast tumors. Trametinib is a specific mitogen-activated protein kinase inhibitor, approved for the treatment of metastatic melanoma. The aim of this study was to examine the synergistic effects of auranofin and trametinib on apoptosis in MCF-7 human breast cancer cells. The combination treatment inhibited cancer cell proliferation and induced cell cycle arrest at the sub-G1 phase and apoptosis via poly (ADP-ribose) polymerase cleavage and caspase-3/7 activation. It is noteworthy that this treatment significantly increased p38 mitogen-activated protein kinase (MAPK) phosphorylation to induce mitochondrial stress, subsequently promoting cancer cell apoptosis through release of apoptosis-inducing factor. Further data demonstrated that combined treatment significantly induced increase in nuclear translocation of AIF. These results indicated that activation of the p38 MAPK signaling pathway and mitochondrial apoptosis may contribute to the synergistic consequences in MCF-7 cells. Collectively, our data demonstrated that combined treatment with auranofin and trametinib exhibited synergistic breast cancer cell death and this combination might be utilized as a novel therapeutic strategy for breast cancer.