Apoptosis In Triple-negative Breast Cancer Cells Research Articles

Inhibition of miR-483-5p improves the proliferation, invasion and inflammatory response of triple-negative breast cancer cells by targeting SOCS3.

microRNAs (miRs) have been indicated to serve oncogenic or tumor suppressor roles. However, the role of miR-483-5p in breast cancer and its associated molecular mechanisms remain unclear. In the present study, compared with adjacent normal tissues and MCF-10a cells, the expression level of miR-483-5p was upregulated in triple-negative breast cancer (TNBC) tissues and TNBC cell lines. Bioinformatic analysis and luciferase reporter assay confirmed the presence of miR-483-5p binding sites in the 3'-untranslated region of suppressor of cytokine signaling 3 (SOCS3). In addition, the expression level of SOCS3 protein in TNBC tissues was markedly lower compared with in adjacent tissues, and miR-483-5p expression was negatively correlated with SOCS3 expression in TNBC tissues. Cell proliferation and flow cytometry assays indicated that knockdown of miR-483-5p inhibited the proliferation and promoted apoptosis in the TNBC cell line BT-549. This effect was markedly attenuated by SOCS3 small interfering (si)RNA transfection. Additionally, wound healing and Transwell assays demonstrated that SOCS3 siRNA reversed the inhibitory effects of miR-483-5p inhibitor on the migration and invasion of BT-549 cells. Moreover, the decrease in miR-483-5p expression significantly reduced the secretion of TNF-α, IL-6, IL-1β and monocyte chemoattractant protein-1 in BT-549 cells, while SOCS3 siRNA could partially reverse this effect. Additionally, SOCS3 overexpression reversed the effects of miR-483-5p mimic on the proliferation, migration, invasion and inflammation of BT-549 cells. Taken together, these data demonstrated that the inhibition of miR-483-5p could inhibit the proliferation, migration, invasion and inflammatory response, while promoting the apoptosis of TNBC cells by negatively regulating SOCS3. miR-483-5p may be a potential target for TNBC therapy.

Ruyiping extract reduces lung metastasis in triple negative breast cancer by regulating macrophage polarization

Lung metastasis of Triple-negative breast cancer (TNBC) causes severe breath-related events and poor prognosis. Ruyiping (RYP), a traditional Chinese medicine prescription, is used to treat breast cancer lung metastasis in clinical practice. This study was to explore the anti-lung-metastatic activities and mechanism of RYP extract by regulating macrophage polarization. The results showed that RYP can inhibit the viability and induce the apoptosis of TNBC cells. In in vitro experiments, RYP significantly inhibited the invasion and migration ability of TNBC cells promoted by M2, the subtype of macrophage which increased TNBC metastasis related genes. In in vivo experiments, RYP reduced the TNBC progression and lung metastasis. M2/M1 ration in the lung and M2 in the tumor was reduced by RYP, as well as M2 master regulator Stat6. Therefore, RYP extract may exhibit anti-lung metastasis function by reducing M2 in both tumor and lung through reducing Stat6.

Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer

RNA-binding proteins (RBPs) are critical regulators of post-transcriptional gene expression, and aberrant RBP-RNA interactions can promote cancer progression. Here, we interrogate the function of RBPs in cancer using pooled CRISPR-Cas9 screening and identify 57 RBP candidates with distinct roles in supporting MYC-driven oncogenic pathways. We find that disrupting YTHDF2-dependent mRNA degradation triggers apoptosis in triple-negative breast cancer (TNBC) cells and tumors. eCLIP and m6A sequencing reveal that YTHDF2 interacts with mRNAs encoding proteins in the MAPK pathway that, when stabilized, induce epithelial-to-mesenchymal transition and increase global translation rates. scRibo-STAMP profiling of translating mRNAs reveals unique alterations in the translatome of single cells within YTHDF2-depleted solid tumors, which selectively contribute to endoplasmic reticulum stress-induced apoptosis in TNBC cells. Thus, our work highlights the therapeutic potential of RBPs by uncovering a critical role for YTHDF2 in counteracting the global increase of mRNA synthesis in MYC-driven breast cancers.

LINC01234 aggravates cell growth and migration of triple-negative breast cancer by activating the Wnt pathway.

Triple-negative breast cancer (TNBC) is a common cancer with increasing incidence and mortality in female. Increasing studies have revealed that long noncoding RNAs (lncRNAs) are novel molecules regulating tumors. Long intergenic non-protein coding RNA 1234 (LINC01234) has been demonstrated to function as an oncogene in several tumors. However, the role of LINC01234 in TNBC remains unelucidated. Herein, RT-qPCR showed that LINC01234 expression was upregulated in both TNBC tissues and cell lines. Functionally, knockdown of LINC01234 suppressed proliferation, migration, invasion, epithelial-mesenchymal transition (EMT) process, and promoted apoptosis in TNBC cells. Xenograft mouse models revealed that LINC01234 downregulation inhibited TNBC tumor growth in vivo. Furthermore, LINC01234 was transcriptionally elevated by Sp1 transcription factor (SP1) in TNBC cells. Mechanistically, LINC01234 interacted with miR-525-5p and miR-525-5p targeted MEIS2. Rescue assays manifested that MEIS2 overexpression rescued the cellular processes inhibited by silenced LINC01234. Moreover, we validated that LINC01234 regulated the activation of the Wnt pathway through modulating MEIS2 in TNBC cells. In conclusion, LINC01234 aggravated TNBC cell growth, migration, invasion and EMT by modulating the miR-525-5p/MEIS2 axis and activating the Wnt/β-catenin signaling pathway.

LncRNA SNHG11 aggravates cell proliferation and migration in triple-negative breast cancer via sponging miR-2355-5p and targeting CBX5.

Triple-negative breast cancer (TNBC) is one of the most common malignances worldwide. Concurrently, the incidence of TNBC has continued to rise in recent years. It is reported that long non-coding RNAs (lncRNAs) are involved in biological processes in numerous cancers including TNBC. Small nucleolar RNA host gene 11 (SNHG11) has already been studied and reported in some cancers. However, the role of SNHG11 in TNBC remains unknown. RT-qPCR was used to measure gene expression in the current study. CCK-8, colony formation, flow cytometry, Transwell and western blotting experiments were also performed to determine the biological function of SNHG11 in TNBC cells. Luciferase reporter and RIP assays were performed to measure relationship between genes. In the present study, the results indicated SNHG11 was highly expressed in TNBC tissues and cell lines. Moreover, SNHG11 aggravated cell proliferation and migration, and whereas it attenuated cell apoptosis in TNBC. Furthermore, SNHG11 sponged microRNA 2355-5p (miR-2355-5p) in TNBC. Silencing SNHG11 increased miR-2355-5p expression. In addition, chromobox 5 (CBX5) was identified to be targeted by miR-2355-5p in TNBC. It was also suggested that CBX5 silencing suppressed cell proliferation and migration. Furthermore, overexpressed CBX5 recovered the inhibitive influence of SNHG11 silencing on proliferative and migrative abilities of TNBC cells. Overall, SNHG11 acted as a tumor promoter in TNBC and regulated TNBC cell growth by modulating the miR-2355-5p/CBX5 axis, which indicated that it may be used as a biomarker for TNBC treatment.

Hsa_circRNA_102229 facilitates the progression of triple-negative breast cancer via regulating the miR-152-3p/PFTK1 pathway.

BackgroundIncreasing evidence has suggested that circular RNAs (circRNAs) may act as an important regulatory factor in tumor progression. However, how circRNAs exert their functions in triple‐negative breast cancer (TNBC) remains not clearly understood.MethodsFirst, circRNA microarrays were conducted to identify aberrantly expressed circRNAs in TNBC tissues. Kaplan–Meier survival analysis was conducted to calculate the correlation between the level of hsa_circRNA_102229 and outcomes of patients with TNBC. The effect of hsa_circRNA_102229 and serine/threonine‐protein kinase PFTAIRE 1 (PFTK1) on TNBC cells was clarified by cell counting kit‐8, transwell and wound healing assays, as well as by a flow cytometry. The molecular mechanism of hsa_circRNA_102229 was clarified through bioinformatics, a dual‐luciferase reporter assay, western blotting, fluorescence in situ hybridization and real‐time polymerase chain reaction. Tumor xenograft experiments were performed to analyze growth and metastasis of TNBC in vivo.ResultsIn TNBC tissues and cells, hsa_circ_102229 was remarkably up‐regulated. Patients with TNBC presenting high hsa_circ_102229 exhibited poor prognosis. Moreover, hsa_circ_102229 could promote the migration, proliferation and invasion, whereas it inhibited the apoptosis of TNBC cells. Furthermore, hsa_circ_102229 directly targeted miR‐152‐3p and could regulate the expression of PFTK1 by targeting miR‐152‐3p. Rescue assays suggested that hsa_circ_102229 may exert its function in TNBC cells by regulating PFTK1. Additionally, knockdown of hsa_circ_102229 slowed down TNBC tumorigenesis and lung metastasis in a tumor xenograft animal model.ConclusionsHsa_circ_102229 might serve as a competing endogenous RNA (ceRNA) to modulate PFTK1 expression via regulating miR‐152‐3p to affect the functions of TNBC cells. Hsa_circ_102229 acts as a newly discovered biomarker for TNBC treatment.

Carbon nanotubes (CNT)-loaded ginsenosides Rb3 suppresses the PD-1/PD-L1 pathway in triple-negative breast cancer.

Carbon nanotubes (CNTs), as advanced nanotechnology with specific properties and structures, have presented practical drug delivery properties. Ginsenoside Rg3 is a component of puffed ginseng and demonstrates anti-cancer activities. To explore the effect of CNTs-loaded Rg3 (Rg3-CNT) on the PD-1/PD-L1 signaling and the development of triple-negative breast cancer (TNBC). Our data revealed that Rg3 inhibited the cell viability of TNBC cells, in which Rg3-CNT further enhanced this effect in the system. Similarly, the colony formation of TNBC cells was decreased by Rg3, while Rg3-CNT could reinforce its effect in the cells. Besides, the treatment of Rg3 induced apoptosis of TNBC cells, in which Rg3-CNT treatment further increased the phenotype in the cells. Remarkably, Rg3-CNT, but not Rg3, attenuated PD-L1 expression in TNBC cells. Rg3-CNT decreased the PD-L1 upregulation induced by interferon-γ (IFN-γ) in breast cancer cells. Importantly, Rg3-CNT was able to reduce PD-1 expression in activated T cells. Specifically, Rg3-CNT reduced the PD-1/PD-L1 axis in a T cell/triple-negative TNBC cell co-culture system. Moreover, the levels of IFN-γ, interleukins-2 (IL-2), interleukins-9 (IL-9), interleukins-10 (IL-10), interleukins-22 (IL-22), and interleukins-23 (IL-23) were significantly stimulated in the activated T cells, while the treatment of Rg3-CNT could reverse these phenotypes in the cells. Rg3-CNT attenuated the TNBC cell growth in vivo. The Rg3-CNT improved the anti-cancer effect of Rg3 toward TNBC by inhibiting the PD-1/PD-L1 axis. Our finding provides new insights into the mechanism by which Rg3-CNT attenuates the development of TNBC. Rg3-CNT may be applied as the potential therapeutic strategy for immunotherapy of TNBC.

Evaluation of the Cytotoxic Effects of the Novel Antineoplastic Agent 1,4,5-Oxathiazinane-4,4-dioxide on Triple Negative Breast Cancer Cells.

Adjuvant therapeutic options are limited for triple negative breast cancer (TNBC). Thus, we evaluated the cytotoxic effects of the newly synthesized antineoplastic agent 1,4,5-Oxathiazinane-4,4-dioxide (OTD) on TNBC cells as a potential cancer therapeutic strategy. TNBC primary BT-20 and metastatic MDA-MB-231 cell lines were treated with increasing concentrations of OTD for various time periods to assess cell viability. Cell necrosis, apoptosis, necroptosis, autophagy, and ROS generation were evaluated using assay kits or specific inhibitors. Treatment with OTD resulted in a dose- and time-dependent cell death of TNBC BT-20 and MDA-MB-231 cells. OTD also dose-dependently arrested TNBC cell proliferation. Notably, treatment with OTD induced both necrosis and apoptosis of TNBC cells, while the pan-caspase inhibitor Z-VAD-FMK partially attenuated OTD-induced cell death. Importantly, abrogated OTD-induced cell death was observed in the presence of the ROS scavenger N-acetylcysteine (NAC), whereas enhanced OTD-induced cell death was observed after the addition of the glutathione synthesis inhibitor BSO, indicating OTD-induced killing of TNBC cells via a reactive oxygen species-dependent mechanism. OTD is strongly cytotoxic to both primary and metastatic TNBC cells, possibly by inducing multiple cell death pathways.

Dezocine, An Opioid Analgesic, Exerts Antitumor Effects in Triple-Negative Breast Cancer by Targeting Nicotinamide Phosphoribosyltransferase

Opioids are a potential adjuvant treatment for certain cancers; while they are primarily used to relieve chronic pain, these drugs may also affect cancer progression and recurrence. Dezocine is one opioid commonly used in China, but its effects on cancer cells are unknown. Here, we demonstrated the inhibitory effect of dezocine on triple-negative breast cancer (TNBC) cells, and determined the underlying molecular mechanism. We found that dezocine suppressed cell proliferation, migration and invasion, and induced apoptosis in TNBC cells. Xenograft models demonstrated the inhibitory effects of dezocine treatment on TNBC tumor growth in vivo. The anticancer effects of dezocine were independent of opioid receptors, which are not highly expressed by normal breast or breast cancer tissues. A pull-down assay and LC-MS/MS analysis indicated that dezocine directly targets NAMPT: computer modeling verified that the free energy of dezocine kinetically bound into the pocket of NAMPT was −17.4 kcal/mol. Consequently, dezocine treatment inhibited NAMPT enzyme activity, resulting in cellular NAD abolishment. We confirmed the dezocine-induced inhibition of cell proliferation by both NAMPT knockdown and upon treatment with the inhibitor FK866. Our results suggest that both dezocine and NAMPT might represent novel therapeutic targets for TNBC.

Long non‑coding RNA SChLAP1 regulates the proliferation of triple negative breast cancer cells via the miR‑524‑5p/HMGA2 axis

Long non-coding RNA (lncRNA) second chromosome locus associated with prostate-1 (SChLAP1), also named LINC00913, has been reported to accelerate the carcinogenesis of prostate cancer. The aim of this study was to explore the role and mechanism of SChLAP1 in triple negative breast cancer (TNBC). The expression of SChLAP1 in TNBC tissues and cells was determined by reverse transcription quantitative PCR. The effects of SChLAP1 on the growth of TNBC cells was evaluated by detecting cell viability, colony formation and apoptosis. The present study determined that SChLAP1 was upregulated in TNBC tissues and was associated with the long-distant lymph node metastasis of patients with TNBC. Knockdown of SChLAP1 significantly inhibited cell viability and colony formation, and triggered apoptosis of TNBC cells. Bioinformatics analysis suggested that SChLAP1 acted as a sponge of microRNA (miR)-524-5p and negatively modulated the expression of miR-524-5p. An inverse correlation was also identified between the expression levels of SChLAP1 and miR-524-5p in TNBC tissues. Furthermore, the results demonstrated that SChLAP1 interacted with miR-524-5p, and subsequently regulated the expression level of High Mobility Group AT-Hook 2 (HMGA2) in TNBC cells. It was also found that the overexpression of HMGA2 rescued the suppressed viability of TNBC cells induced by SChLAP1 knockdown. In conclusion, the present findings demonstrated that SChLAP1 modulated the malignant tumor behaviors of TNBC cells by regulating HMGA2 and subsequently restraining miR-524-5p.

An in vitro study on the reversal of epithelial to mesenchymal transition by brusatol and its synergistic properties in triple-negative breast cancer cells.

Taxane based conventional chemotherapy serves as the standard treatment regimen for triple-negative breast cancer (TNBC). However, the efficacy is plateaued due to toxicities, chemoresistance and metastasis. Hence, the development of new therapies that provide long-term cover is needed. Brusatol, a natural quassinoid, has been implicated to inhibit the migration and proliferation of metastatic cells in lung and liver carcinoma, but its efficacy in TNBC has not been explored. The growth inhibitory activity on TNBC cells was measured using MTT assay and flow cytometry. Epithelial to mesenchymal transition (EMT) and apoptotic markers were quantified using western blotting. The caspases using Calorimetric assay. Brusatol along with paclitaxel showed an enhanced growth inhibitory activity and a combined synergistic effect. In addition, brusatol was also observed to inhibit the invasion, migratory potential of TNBC cells. Mechanistically, brusatol and its combination were observed to decrease the matrix metalloproteinase (MMP) and a modest increase in the reactive oxygen species (ROS) production. Furthermore, brusatol treatment activated both intrinsic and extrinsic pathways with morphological changes of apoptosis in TNBC cells. This is the first in vitro report demonstrating antineoplastic, anti-EMT and synergistic activity of brusatol and in combination with paclitaxel in TNBC cell. Further in-vivo studies are needed to substantiate the above findings.

LncRNA MIR503HG inhibits cell proliferation and promotes apoptosis in TNBC cells via the miR-224-5p/HOXA9 axis

Triple-negative breast cancer (TNBC) is a highly invasive subtype of breast cancer. This study investigated the molecular mechanism and influences of MIR503HG, miR-224-5p, and homeobox A9 (HOXA9) on TNBC cell growth and migration. Dual-luciferase reporter gene and RNA immunoprecipitation were performed to examine the regulation of MIR503HG, miR-224-5p, and HOXA9. Cell proliferation, apoptosis, migration, and invasion were evaluated by colony formation, flow cytometry, and Transwell assays. Finally, nude mice were employed to investigate the influence of MIR503HG on TNBC tumor growth. HOXA9 protein levels were detected by immunohistochemical staining. MIR503HG and HOXA9 expression were reduced in TNBC, while miR-224-5p was increased. Overexpression of MIR503HG or HOXA9 reduced the cell migration ability and proliferation and promoted apoptosis, and knockdown of MIR503HG or overexpression of miR-224-5p exhibited the opposite effects. Furthermore, MIR503HG promoted HOXA9 expression by inhibiting miR-224-5p. Overexpression of miR-224-5p reversed the effects of MIR503HG overexpression on TNBC cells, while overexpression of HOXA9 reversed the effect of MIR503HG knockdown. Additionally, an in vivo study proved that MIR503HG inhibited TNBC tumor growth via the miR-224-5p/HOXA9 axis. MIR503HG inhibited cell proliferation and promoted the apoptosis of TNBC cells via the miR-224-5p/HOXA9 axis, which may function as a novel target for the treatment of TNBC.

Dual Inhibition of AKT and MEK Pathways Potentiates the Anti-Cancer Effect of Gefitinib in Triple-Negative Breast Cancer Cells.

Simple SummaryTriple-negative breast cancer (TNBC) is an intractable subset of breast cancer without an efficient therapeutic strategy due to the lack of tractable targets, such as the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Activation and/or amplification of epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK)/ extracellular signal-regulated kinase (ERK) pathways is known in TNBC; however, interventions for these targets have not been successful to date. To explore a combinatorial strategy with existing clinical/preclinical protein kinase inhibitors (PKIs) in TNBC cells, we performed a series of cytotoxicity (cell viability) screenings with various PKIs in the presence figure of an EGFR inhibitor, gefitinib. The dual inhibition of AKT and MEK with gefitinib reduced the proliferation and colony formation of TNBC cells by inducing apoptosis. Our finding suggests a new approach for treating TNBC with a multiplex combination of PKIs.There is an unmet medical need for the development of new targeted therapeutic strategies for triple-negative breast cancer (TNBC). With drug combination screenings, we found that the triple combination of the protein kinase inhibitors (PKIs) of the epidermal growth factor receptor (EGFR), v-akt murine thymoma viral oncogene homolog (AKT), and MAPK/ERK kinase (MEK) is effective in inducing apoptosis in TNBC cells. A set of PKIs were first screened in combination with gefitinib in the TNBC cell line, MDA-MB-231. The AKT inhibitor, AT7867, was identified and further analyzed in two mesenchymal stem-like (MSL) subtype TNBC cells, MDA-MB-231 and HS578T. A combination of gefitinib and AT7867 reduced the proliferation and long-term survival of MSL TNBC cells. However, gefitinib and AT7867 induced the activation of the rat sarcoma (RAS)/ v-raf-1 murine leukemia viral oncogene homolog (RAF)/MEK/ extracellular signal-regulated kinase (ERK) pathway. To inhibit this pathway, MEK/ERK inhibitors were further screened in MDA-MB-231 cells in the presence of gefitinib and AT7867. As a result, we identified that the MEK inhibitor, PD-0325901, further enhanced the anti-proliferative and anti-clonogenic effects of gefitinib and AT7867 by inducing apoptosis. Our results suggest that the dual inhibition of the AKT and MEK pathways is a novel potential therapeutic strategy for targeting EGFR in TNBC cells.

Sauropus androgynus (L.) leaf phytochemical activated biocompatible zinc oxide nanoparticles: An antineoplastic agent against human triple negative breast cancer and a potent nanocatalyst for dye degradation

The present study delineates the biosynthesis of ZnOSA NPs by availing S. androgynous (L.) aqueous leaf extract. The formation of ZnOSA NPs was substantiated by FT-IR and UV–visible spectroscopy which was further corroborated by the elemental composition study through EDS spectroscopy. The FE-SEM and HRTEM micrographs have revealed the formation of NPs with different shapes and sizes ranging from 12 to 23 nm. The BET isotherms obtained have manifested the mesoporous nature of ZnOSA NPs. The in-vitro cytotoxicity studies of ZnOSA NPs carried out on MDAMB468 human triple-negative breast cancer (TNBC) and NIH3T3 mouse fibroblast cells have evinced their potential cytotoxic effect (75.98 ± 1.07) on cancer cells sparing the normal cells. Further, the results of the AO-EB dual staining assay indicated early apoptosis in TNBC cells by displaying greenish yellow-fluorescence in the nuclei at a IC50 concentration of 53.79 µg/mL of NPs. Additionally; the human erythrocyte membrane stabilization assay has corroborated the haemocompatibility of ZnOSA NPs by exhibiting a % HRBCMS up to 89.15 ± 0.02%. Furthermore, the photocatalytic experiments performed on Methylene Blue dye have revealed the excellent degradation efficiencies of ZnOSA NPs up to 88.01% with high stability and reusability tested during 4 catalytic cycles. Thus, the obtained results have shown greater potential in the anticancer and photocatalytic dye degradation activities of bio-fabricated ZnOSA NPs.

Resveratrol Mediates the Apoptosis of Triple Negative Breast Cancer Cells by Reducing POLD1 Expression

Resveratrol (RSV) is known to possess anticancer properties in many types of cancers like breast cancer, in which POLD1 may serve as a potential target. However, the anticancer mechanism of RSV on triple negative breast cancer (TNBC) remains unclear. In the present study, the antitumor effects and mechanism of RSV on TNBC cells were analyzed by RNA sequencing (RNA-seq), which was then verified via cell counting kit-8 (CCK8), immunofluorescence, immunohistochemistry, Western Blot (WB), flow cytometry, and hematoxylin-eosin (HE) staining. According to the corresponding findings, the survival rate of MDA-MB-231 cells gradually decreased as RSV treatment concentration increased. The RNA-seq analysis results demonstrated that genes affected by RSV treatment were mainly involved in apoptosis and the p53 signaling pathway. Moreover, apoptosis of MDA-MB-231 cells induced by RSV was observed to be mainly mediated by POLD1. When treated with RSV, the expression levels of full length PARP1, PCNA, and BCL-2 were found to be significantly reduced, and the expression level of Cleaved-PARP1 as well as Cleaved-Caspase3 increased significantly. Additionally, the mRNA expression of POLD1 was significantly reduced after treatment with RSV, and the protein expression level was also inhibited by RSV in a concentration-dependent manner. The prediction of domain interaction suggested that RSV may bind to at least five functional domains of the POLD1 protein (6s1m, 6s1n, 6s1o, 6tny and 6tnz). Furthermore, after RSV treatment, the anti-apoptotic index (PCNA, BCL-2) of MDA-MB-231 cells was found to decrease while the apoptosis index (caspase3) increased. Moreover, the overexpression of POLD1 reduced the extent of apoptosis observed in MDA-MB-231 cells following RSV treatment. Moreover, animal experimental results showed that RSV had a significant inhibitory effect on the growth of live tumors, while POLD1 overexpression was shown to antagonize this inhibitory effect. Accordingly, this study’s findings reveal that RSV may promote the apoptosis of TNBC cells by reducing the expression of POLD1 to activate the apoptotic pathway, which may serve as a potential therapy for the treatment of TNBC.

The Oxygen-Generating Calcium Peroxide-Modified Magnetic Nanoparticles Attenuate Hypoxia-Induced Chemoresistance in Triple-Negative Breast Cancer.

Simple SummaryTumor hypoxia is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lack of target. Therefore, chemotherapy is the only approved systemic treatment in TNBC. Here, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. CaO2-MNPs promoted ubiquitination and protein degradation of hypoxia-inducible factor 1α (HIF-1α). Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. CaO2-MNPs in combination with doxorubicin showed a stronger tumor-suppressive effect on TNBC compared to the doxorubicin treatment alone in an orthotopic mouse model. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1α expression to improve the efficiency of chemotherapy in TNBC.Cancer response to chemotherapy is regulated not only by intrinsic sensitivity of cancer cells but also by tumor microenvironment. Tumor hypoxia, a condition of low oxygen level in solid tumors, is known to increase the resistance of cancer cells to chemotherapy. Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Due to lack of target in TNBC, chemotherapy is the only approved systemic treatment. We evaluated the effect of hypoxia on chemotherapy resistance in TNBC in a series of in vitro and in vivo experiments. Furthermore, we synthesized the calcium peroxide-modified magnetic nanoparticles (CaO2-MNPs) with the function of oxygen generation to improve and enhance the therapeutic efficiency of doxorubicin treatment in the hypoxia microenvironment of TNBC. The results of gene set enrichment analysis (GSEA) software showed that the hypoxia and autophagy gene sets are significantly enriched in TNBC patients. We found that the chemical hypoxia stabilized the expression of hypoxia-inducible factor 1α (HIF-1α) protein and increased doxorubicin resistance in TNBC cells. Moreover, hypoxia inhibited the induction of apoptosis and autophagy by doxorubicin. In addition, CaO2-MNPs promoted ubiquitination and protein degradation of HIF-1α. Furthermore, CaO2-MNPs inhibited autophagy and induced apoptosis in TNBC cells. Our animal studies with an orthotopic mouse model showed that CaO2-MNPs in combination with doxorubicin exhibited a stronger tumor-suppressive effect on TNBC, compared to the doxorubicin treatment alone. Our findings suggest that combined with CaO2-MNPs and doxorubicin attenuates HIF-1α expression to improve the efficiency of chemotherapy in TNBC.

Lamin B2 promotes the progression of triple negative breast cancer via mediating cell proliferation and apoptosis.

Triple negative breast cancer (TNBC) is a more common type of breast cancer with high distant metastasis and poor prognosis. The potential role of lamins in cancer progression has been widely revealed. However, the function of lamin B2 (LMNB2) in TNBC progression is still unclear. The present study aimed to investigate the role of LMNB2 in TNBC. The cancer genome atlas (TCGA) database analysis and immunohistochemistry (IHC) were performed to examine LMNB2 expression levels. LMNB2 short hairpin RNA plasmid or lentivirus was used to deplete the expression of LMNB2 in human TNBC cell lines including MDA-MB-468 and MDA-MB-231. Alterations in cell proliferation and apoptosis in vitro and the nude mouse tumorigenicity assay in vivo were subsequently analyzed. The human TNBC tissues shown high expression of LMNB2 according to the bioinformation analysis and IHC assays. LMNB2 expression was correlated with the clinical pathological features of TNBC patients, including pTNM stage and lymph node metastasis. Through in vitro and in vivo assays, we confirmed LMNB2 depletion suppressed the proliferation and induced the apoptosis of TNBC cells, and inhibited tumor growth of TNBC cells in mice, with the decrease in Ki67 expression or the increase in caspase-3 expression. In conclusion, LMNB2 may promote TNBC progression and could serve as a potential therapeutic target for TNBC treatment.

MicroRNA-598 inhibits the growth of triple negative breast cancer cells by targeting JAG1.

Triple-negative breast cancer (TNBC) has an aggressive phenotype and a poor outcome. The discovery that dysregulated microRNAs (miRNAs) play an important role in tumor progression has led to the suggestion that miRNAs (miRs) could be a potential target for the treatment of TNBC. In the present study, it was demonstrated that miR-598 expression was significantly decreased in TNBC tissues and was related to the degree of lymph node metastasis of patients with TNBC. Ectopic expression of miR-598 suppressed viability and colony formation, as well as increased the apoptosis of TNBC cells. To further understand the functional mechanism of action underlying miR-598 in TNBC, targets of miR-598 were predicted with the miRDB bioinformatics tool. Jagged 1 (JAG1) was identified as a direct target of miR-598, possessing a binding site for miR-598 in its 3'-untranslated region. Overexpression of miR-598 inhibited the expression of JAG1 in TNBC cells. In addition, JAG1 was highly expressed in TNBC tissues and its expression was negatively correlated with the expression of miR-598. Overexpression of JAG1 significantly attenuated the inhibitory effects of miR-598 on the proliferation and colony formation of TNBC cells. Collectively, these results provided novel insights into the functional mechanism of action for the miR-598/JAG1 pathway in the development of TNBC.

Unravelling the human triple negative breast cancer suppressive activity of biocompatible zinc oxide nanostructures influenced by Vateria indica (L.) fruit phytochemicals

The present study delineates the biosynthesis of ZnOVI nanostructures by using aqueous fruit extract of V. indica. The study has disclosed the role of V. indica fruit extract as both reducing and capping agents, ushering the formation of ZnOVI nanostructures with distinct morphologies. The formation of ZnOVI nanostructures was corroborated by FT-IR and UV–visible spectroscopy which was further substantiated by the elemental composition study through EDS spectroscopy. The nanostructures were also investigated by Rietveld refinement of PXRD data, FE-SEM, and BET analysis. The morphology, size, and surface area were found to be precursor stoichiometry dependent. The in-vitro cytotoxicity study of ZnOVI nanostructures carried out on MDA-MB468 human triple-negative breast cancer (TNBC) cells has revealed their potential cytotoxicity (91.18 ± 1.98). MTT assay performed on the NIH3T3 mouse fibroblast cells has unfolded the non-toxic nature of ZnOVI nanostructures. Additionally, the results of the AO-EB dual staining assay indicated early apoptosis in TNBC cells by displaying greenish yellow-fluorescence in the nuclei. Reactive oxygen species (ROS) measurement study has confirmed the elevated intracellular levels of ROS, supporting the oxidative-stress induced cytotoxicity in ZnOVI nanostructures treated TNBC cells. Furthermore, the haemocompatibility of ZnOVI nanostructures was evaluated using human erythrocytes. Thus, the obtained results have shown greater potential in the anticancer activity of bio-fabricated ZnOVI nanostructures.

HOXD Antisense Growth-Associated Long Noncoding RNA Promotes Triple-Negative Breast Cancer Progression by Activating Wnt Signaling Pathway.

PurposeTriple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer owing to high heterogeneity, aggressive nature, and lack of treatment options, which has a substantial deleterious effect on patients' lives. HOXD antisense growth-associated long noncoding RNA (lncRNA) (HAGLR) plays tumor-promoting roles in many cancers. In this study, we aimed to explore the role of HAGLR in TNBC.MethodsQuantitative real-time polymerase chain reaction assays were used to examine the expression of RNAs. Functional experiments were conducted to test the biological behavior of TNBC cells. Moreover, MS2-RNA immunoprecipitation, luciferase reporter, and RNA pull-down assays were conducted to verify the binding relationship between HAGLR, microRNA-143-5p (miR-143-5p), and serine- and arginine-rich splicing factor 1 (SRSF1).ResultsHAGLR was found to be highly expressed in TNBC tissues and cells, and inhibiting HAGLR suppressed cell proliferation, migration, and invasion and promoted cell apoptosis in TNBC. Meanwhile, miR-93-5p was shown to bind to HAGLR and SRSF1. In addition, SRSF1 plays an oncogenic role in TNBC. Importantly, HAGLR could activate the Wnt signaling pathway by sponging miR-93-5p to upregulate SRSF1; thus, accelerating TNBC progression.ConclusionHAGLR could promote the progression of TNBC through the miR-93-5p/SRSF1 axis to activate the Wnt signaling pathway.