Breast Cancer Proliferation Research Articles

FOXA1 O-GlcNAcylation-mediated transcriptional switch governs metastasis capacity in breast cancer.

FOXA1, a transcription factor involved in epigenetic reprogramming, is crucial for breast cancer progression. However, the mechanisms by which FOXA1 achieves its oncogenic functions remain elusive. Here, we demonstrate that the O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) of FOXA1 promotes breast cancer metastasis by orchestrating the transcription of numerous metastasis regulators. O-GlcNAcylation at Thr432, Ser441, and Ser443 regulates the stability of FOXA1 and promotes its assembly with chromatin. O-GlcNAcylation shapes the FOXA1 interactome, especially triggering the recruitment of the transcriptional repressor methyl-CpG binding protein 2 and consequently stimulating FOXA1 chromatin-binding sites to switch to chromatin loci of adhesion-related genes, including EPB41L3 and COL9A2. Site-specific depletion of O-GlcNAcylation on FOXA1 affects the expression of various downstream genes and thus inhibits breast cancer proliferation and metastasis both in vitro and in vivo. Our data establish the importance of aberrant FOXA1 O-GlcNAcylation in breast cancer progression and indicate that targeting O-GlcNAcylation is a therapeutic strategy for metastatic breast cancer.

Inhibition of PPARγ by BZ26, a GW9662 derivate, attenuated obesity-related breast cancer progression by inhibiting the reprogramming of mature adipocytes into to cancer associate adipocyte-like cells.

Obesity has been associated with the development of 13 different types of cancers, including breast cancer. Evidence has indicated that cancer-associated adipocytes promote the proliferation, invasion, and metastasis of cancer. However, the mechanisms that link CAAs to the progression of obesity-related cancer are still unknown. Here, we found the mature adipocytes in the visceral fat of HFD-fed mice have a CAAs phenotype but the stromal vascular fraction of the visceral fat has not. Importantly, we found the derivate of the potent PPARγ antagonist GW9662, BZ26 inhibited the reprogramming of mature adipocytes in the visceral fat of HFD-fed mice into CAA-like cells and inhibited the proliferation and invasion of obesity-related breast cancer. Further study found that it mediated the browning of visceral, subcutaneous and perirenal fat and attenuated inflammation of adipose tissue and metabolic disorders. For the mechanism, we found that BZ26 bound and inhibited PPARγ by acting as a new modulator. Therefore, BZ26 serves as a novel modulator of PPARγ activity, that is, capable of inhibiting obesity-related breast cancer progression by inhibiting of CAA-like cell formation, suggesting that inhibiting the reprogramming of mature adipocytes into CAAs or CAA-like cells may be a potential therapeutic strategy for obesity-related cancer treatment.

A New Quinone-Based Inhibitor of Mitochondrial Complex I in D-Conformation, Producing Invasion Reduction and Sensitization to Venetoclax in Breast Cancer Cells.

Mitochondrial Complex I plays a crucial role in the proliferation, chemoresistance, and metastasis of breast cancer (BC) cells. This highlights it as an attractive target for anti-cancer drugs. Using submitochondrial particles, we identified FRV-1, an ortho-carbonyl quinone, which inhibits NADH:duroquinone activity in D-active conformation and reduces the 3ADP state respiration dependent on Complex I, causing mitochondrial depolarization, ATP drop, increased superoxide levels, and metabolic remodeling towards glycolysis in BC cells. Introducing methyl groups at FRV-1 structure produced analogs that acted as electron acceptors at the Complex I level or increased the inhibitory effect of FCCP-stimulated oxygen consumption rate, which correlated with their redox potential, but increased toxicity on RMF-621 human breast fibroblasts was observed. FRV-1 was inactive in the naphthoquinone oxidoreductase 1 (NOQ1)-positive BC cell line, MCF7, but the sensitivity was recovered by dicoumarol, a NOQ1 inhibitor, suggesting that FRV-1 is a NOQ1 substrate. Importantly, FRV-1 selectively inhibited the proliferation, migration, and invasion of NQO1 negative BC cell, MDA-MB-231, in an OXPHOS- and ROS-dependent manner and sensitized it to the BH3 mimetic drug venetoclax. Overall, FRV-1 is a novel Complex I inhibitor in D-active conformation, blocking possibly the re-activation to A-state, producing selective anti-cancer effects in NQO1-negative BC cell lines.

YY1 regulates the proliferation and invasion of triple-negative breast cancer via activating PLAUR.

It is well-established that breast cancer is a highly prevalent malignancy among women, emphasizing the need to investigate mechanisms underlying its pathogenesis and metastasis. In this study, the Gene Expression Omnibus (GEO) database was utilized to conduct differential expression analysis in breast cancer and adjacent tissues. Upregulated genes were selected for prognostic analysis of breast cancer. The expression of urokinase plasminogen activator receptor (uPAR), also known as PLAUR, was assessed using RT-qPCR and western blot. Immunofluorescence staining was employed to determine PLAUR localization. Various cellular processes were analyzed, including proliferation, migration, invasion, apoptosis, and cell cycle. Bioinformatics analysis was used to predict transcription factors of PLAUR, which were subsequently validated in a double luciferase reporter gene experiment. Rescue experiments confirmed the impact of PLAUR on the proliferation, apoptosis, and migration of MDA-MB-231 cells. Furthermore, the effects of PLAUR were evaluated in an orthotopic tumor transplantation and lung metastasis nude mouse model. Our findings substantiated the critical involvement of PLAUR in the progression of triple-negative breast cancer (TNBC) in vitro and among TNBC patients with a poor prognosis. Additionally, we demonstrated Yin Yang-1 (YY1) as a notable transcriptional regulator of PLAUR, whose activation could transcriptionally enhance the proliferation and invasion capabilities of TNBC cells. We also identified the downstream mechanism of PLAUR associated with PLAU, focal adhesion kinase (FAK), and AKT. Overall, these findings offer a novel perspective on PLAUR as a potential therapeutic target for TNBC.

HOXC13 promotes cell proliferation, metastasis and glycolysis in breast cancer by regulating DNMT3A.

Breast cancer (BC) is a life-threatening malignant tumor that affects females more commonly than males. The mechanisms underlying BC proliferation, metastasis and glycolysis require further investigation. Homeobox C13 (HOXC13) is highly expressed in BC; however, the specific mechanisms in BC are yet to be fully elucidated. Therefore, the aim of the present study was to investigate the role of HOXC13 in BC proliferation, migration, invasion and glycolysis. In the present study, the UALCAN database was used to predict the expression levels of HOXC13 in patients with BC. Western blot analysis and reverse transcription-quantitative PCR were used to determine the expression levels of HOXC13 in BC cell lines. Moreover, HOXC13 knockdown was induced using cell transfection, and the viability, proliferation and apoptosis of cells were detected using Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining and flow cytometry. Migration, invasion and epithelial-mesenchymal transition (EMT) were measured using wound healing assay, Transwell assay and western blotting. In addition, XF96 extracellular flux analyzer and corresponding kits were used to detect glycolysis. The JASPAR database was used to predict promoter binding sites for the transcription factors HOXC13 and DNA methyltransferase 3α (DNMT3A). HOXC13 expression was silenced and DNMT3A was simultaneously overexpressed using cell transfection. The results of the present study revealed that HOXC13 expression was significantly elevated in BC tissues and cells. Following HOXC13 knockdown in BC cells, the viability, proliferation, glycolysis, migration, invasion and EMT were significantly decreased, and apoptosis was significantly increased. In addition, HOXC13 positively regulated the transcription of DNMT3A in BC cells, thus playing a regulatory role in the malignant progression of cells. In conclusion, HOXC13 promoted cell viability, proliferation, migration, invasion, EMT and glycolysis in BC by regulating DNMT3A.

Promoting proliferation and tumorigenesis of breast cancer: KCND2's significance as a prognostic factor.

In recent years, the potassium voltage-gated channel subfamily D (KCND) channels, particularly KCND2 (also known as Kv4.2), have been suggested to play a role in a variety of cancers, but their role in breast cancer has not yet been revealed. We analyzed RNA sequencing data from The Cancer Genome Atlas database and the Genotype-Tissue Expression database to investigate the differential expression of KCND2 in breast cancer and normal breast tissue. In addition, we leveraged GO and KEGG analysis techniques to gain a better understanding of the potential functional enrichment of 500 genes related to KCND2. Our findings were validated using collected tissue samples and clinical data from hospitals showed that KCND2 is a crucial independent factor in the prognosis of breast cancer patients. The higher the expression of KCND2, the shorter the survival time of breast cancer patients. Colony formation assay confirmed that KCND2 promotes the proliferation of breast cancer cells, whereas transwell assay and wound healing assay verified that KCND2 promoted breast cancer invasion and migration. In addition, 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry revealed that KCND2 affected the cycle changes of breast cancer cells and contributed to the G1/S phase transition of breast cancer cells. Overall, our study demonstrates that KCND2 holds a promising potential as a significant target for breast cancer diagnosis and therapy.

Novel phenanthrene imidazoles as telomeric G-quadruplex ligands trigger potent immunogenic cell death in triple-negative breast cancer

Immunogenic cell death (ICD) is a typical type of regulated cell demise, and ICD inducers stimulate the immune responses against dead-cell antigens and exert specific antitumor effects. G-quadruplex (G4) binders targeting the telomeres lead to DNA damage response (DDR) and the potential of harnessing the immune system for cancer therapy. However, the immunostimulatory effects of G4 ligands in cancer cells are still seldomly determined. In this study, we rationally designed and synthesized a series of novel phenanthrene imidazoles targeting telomeric G4. Among them, PI-2 was identified as the most promising ligand with high cytotoxicity, cellular uptake efficiency and G4-interacting ability. Cellular studies indicated that PI-2 inhibited the proliferation and migration of both human and mouse triple-negative breast cancer (TNBC) cells. PI-2 triggered the occurrence of DDR and ICD, where the related pathways were further decided. In vivo experiments displayed that PI-2-treated dying cells could be an effective vaccination to reduce tumor burden and promote the infiltration of CD8+ and CD4+ T cells to the tumor microenvironment (TME). To our knowledge, it is the first time to report a DDR-targeted G4 ligand with ICD-inducing ability in immunocompetent animals, which may provide new insights for the development of promising G4-based immunochemotherapeutic agents.

Small patient datasets reveal genetic drivers of non-small cell lung cancer subtypes using machine learning for hypothesis generation

Aim: Many small datasets of significant value exist in the medical space that are being underutilized. Due to the heterogeneity of complex disorders found in oncology, systems capable of discovering patient subpopulations while elucidating etiologies are of great value as they can indicate leads for innovative drug discovery and development. Methods: Two small non-small cell lung cancer (NSCLC) datasets (GSE18842 and GSE10245) consisting of 58 samples of adenocarcinoma (ADC) and 45 samples of squamous cell carcinoma (SCC) were used in a machine intelligence framework to identify genetic biomarkers differentiating these two subtypes. Utilizing a set of standard machine learning (ML) methods, subpopulations of ADC and SCC were uncovered while simultaneously extracting which genes, in combination, were significantly involved in defining the subpopulations. A previously described interactive hypothesis-generating method designed to work with ML methods was employed to provide an alternative way of extracting the most important combination of variables to construct a new data set. Results: Several genes were uncovered that were previously implicated by other methods. This framework accurately discovered known subpopulations, such as genetic drivers associated with differing levels of aggressiveness within the SCC and ADC subtypes. Furthermore, phyosphatidylinositol glycan anchor biosynthesis, class X (PIGX) was a novel gene implicated in this study that warrants further investigation due to its role in breast cancer proliferation. Conclusions: The ability to learn from small datasets was highlighted and revealed well-established properties of NSCLC. This showcases the utility of ML techniques to reveal potential genes of interest, even from small datasets, shedding light on novel driving factors behind subpopulations of patients.

WTAP Mediates NUPR1 Regulation of LCN2 Through m6A Modification to Influence Ferroptosis, Thereby Promoting Breast Cancer Proliferation, Migration and Invasion.

Ferroptosis is involved in various pathophysiological diseases, including triple-negative breast cancer (TNBC). Targeting ferroptosis is considered as a novel anti-TNBC strategy. Nevertheless, the regulatory mechanism of ferroptosis during TNBC progression is unclear. Here, the role of WTAP in ferroptosis during TNBC progression was investigated.The clinicopathological significance of WTAP, NUPR1 and LCN2 was analyzed by Kaplan-Meier method. Cell viability was assessed using MTT assay. Transwell assay was employed to analyze cell migration and invasion. GSH/GSSG and Fe2+ levels in TNBC cells were analyzed using kits. m6A level was examined using m6A dot blot assay. NUPR1 mRNA stability was analyzed using RNA degradation assay. RIP was performed to analyze the interaction between eIF3a and NURP1.Herein, our results revealed that WTAP, NUPR1 and LCN2 expressions were significantly elevated in TNBC. NUPR1 silencing inhibited TNBC cell proliferation, migration and invasion by inducing ferroptosis. NUPR1 positively regulated LCN2 expression in TNBC cells, and LCN2 knockdown induced ferroptosis to suppress TNBC cell malignant behaviors. Our molecular study further revealed that WTAP promoted NUPR1 expression in an m6A-EIF3A mediated manner. And, as expected, WTAP knockdown promoted ferroptosis to suppress TNBC cell malignant behaviors, which were abrogated by NUPR1 overexpression.WTAP upregulated LCN2 by regulation of NUPR1 m6A modification, thereby suppressing ferroptosis to contribute to accelerate TNBC progression. Our study revealed the cancer-promoting effect of WTAP, NUPR1 and LCN2 in TNBC and clarified the relevant mechanism, providing a theoretical basis for developing novel diagnostic and therapeutic strategies for TNBC.

Production of novel recombinant anti-EpCAM antibody as targeted therapy for breast cancer

BackgroundThe utilization of monoclonal antibodies (moAbs), an issue correlated with the biopharmaceutical professions, is developing and maturing. Coordinated with this conception, we produced the appealingly modeled anti-EpCAM scFv for breast cancer tumors. MethodsAfterward cloning and expression of recombinant antibody in Escherichia coli bacteria, the correctness of the desired antibody was checked by western blotting. Flow cytometry was utilized to determine the capacity of the recombinant antibody to append to the desired receptors in the malignant breast cancer (BC)cell line. The recombinant antibody (anti-EpCAM scFv) was examined for preclinical efficacy in reducing tumor growth, angiogenesis, and invasiveness (in vitro- in vivo). FindingsA target antibody-mediated attenuation of migration and invasion in the examined cancer cell lines was substantiated (P-value < 0.05). Grafted tumors from breast cancer in mice indicated significant and compelling suppression of tumor growth and decrement in blood supply in reaction to the recombinant anti-EpCAM intervention. Evaluations of immunohistochemical and histopathological findings revealed an enhanced response rate to the treatment. ConclusionThe desired anti-EpCAM scFv can be a therapeutic tool to reduce invasion and proliferation in malignant breast cancer.

Synthetic Reader-Actuators Targeted to Polycomb-Silenced Genes Block Triple-Negative Breast Cancer Proliferation and Invasion.

Scientists have used pharmacological inhibitors of polycomb proteins to restore the expression of tumor suppressor genes and stop cancer proliferation and invasion. A major limitation of this approach is that key transcriptional activators, such as TP53 and BAF SWI/SNF, are often mutated in cancer. Poor clinical results for polycomb-targeting therapies in solid cancers, including triple-negative breast cancer (TNBC), could discourage the further development of epigenetic monotherapies. Here, we performed epigenome actuation with a synthetic reader-actuator (SRA) that binds trimethylated histone H3 lysine 27 in polycomb chromatin and modulates core transcriptional activators. In SRA-expressing TNBC BT-549 cells, 122 genes become upregulated ≥2-fold, including the genes involved in cell death, cell cycle arrest, and migration inhibition. The SRA-expressing spheroids showed reduced size in Matrigel and loss of invasion. Therefore, targeting Mediator-recruiting regulators to silenced chromatin can activate tumor suppressors and stimulate anti-cancer phenotypes, and further development of robust gene regulators might benefit TNBC patients.

Prox1 Suppresses the Proliferation of Breast Cancer Cells via Direct Inhibition of c-Myc Gene Expression.

Breast cancer is one of the most lethal malignancies in women worldwide and is characterized by rapid growth and low survival rates, despite advances in tumor biology and therapies. Novel therapeutic approaches require new insights into the molecular mechanisms of malignant transformation and progression. To this end, here, we identified Prox1 as a negative regulator of proliferation and tumor-related metabolism in breast cancer. In particular, we showed that breast tumors from human patients exhibited reduced levels of Prox1 expression, while high expression levels of Prox1 were associated with a favorable prognosis in breast cancer patients. Moreover, we experimentally demonstrated that Prox1 was sufficient to strongly suppress proliferation, migration, and the Warburg effect in human breast cancer cells without inducing apoptosis. Most importantly, over-expression of Prox1 inhibited breast tumor growth in vivo in both heterotopic and orthotopic xenograft mouse models. The anti-tumorigenic effect of Prox1 was mediated by the direct repression of c-Myc transcription and its downstream target genes. Consistently, c-Myc over-expression from an artificial promoter that was not targeted by Prox1 reversed Prox1's anti-tumor effects. These findings suggest that Prox1 has a tumor suppressive role via direct transcriptional regulation of c-Myc, making it a promising therapeutic gene for breast cancer.

Identification of PIMREG as a novel prognostic signature in breast cancer via integrated bioinformatics analysis and experimental validation.

Phosphatidylinositol binding clathrin assembly protein interacting mitotic regulator (PIMREG) expression is upregulated in a variety of cancers. However, its potential role in breast cancer (BC) remains uncertain. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to gather relevant information. The expression of PIMREG and its clinical implication in BC were assessed by using Wilcoxon rank-sum test. The prognostic value of PIMREG in BC was evaluated through the Cox regression model and nomogram, and visualized by Kaplan-Meier survival curves. Genes/proteins that interact with PIMREG in BC were also identified through GeneMANIA and MaxLink. Gene set enrichment analysis (GSEA) was then performed. The correlations of the immune cell infiltration and immune checkpoints with the expression of PIMREG in BC were explored via TIMER, TISIDB, and GEPIA. Potential drugs that interact with PIMREG in BC were explored via Q-omic. The siRNA transfection, CCK-8, and transwell migration assay were conducted to explore the function of PIMREG in cell proliferation and migration. PIMREG expression was significantly higher in infiltrating ductal carcinoma, estrogen receptor negative BC, and progestin receptor negative BC. High expression of PIMREG was associated with poor overall survival, disease-specific survival, and progression-free interval. A nomogram based on PIMREG was developed with a satisfactory prognostic value. PIMREG also had a high diagnostic ability, with an area under the curve of 0.940. Its correlations with several immunomodulators were also observed. Immune checkpoint CTLA-4 was significantly positively associated with PIMREG. HDAC2 was found as a potentially critical link between PIMREG and BRCA1/2. In addition, PIMREG knockdown could inhibit cell proliferation and migration in BC. The high expression of PIMREG is associated with poor prognosis and immune checkpoints in BC. HDAC2 may be a critical link between PIMREG and BRCA1/2, potentially a therapeutic target.

RUSC1-AS1 promotes the malignant progression of breast cancer depending on the regulation of the miR-326/XRCC5 pathway.

Many long noncoding RNAs (lncRNAs) are the key regulators for cancer progression, including breast cancer (BC). RUSC1 antisense 1 (RUSC1-AS1) has been found to be highly expressed in BC, but its role and potential molecular mechanism in BC remain to be further elucidated. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to measure RUSC1-AS1, microRNA (miR)-326 and X-ray repair cross-complementing group 5 (XRCC5) expression. Cell proliferation, metastasis, cell cycle, apoptosis and angiogenesis were determined by cell counting kit-8, colony formation, transwell, flow cytometry and tube formation assays. Protein expression was detected by western blot analysis. The targeted relationship between miR-326 and RUSC1-AS1 or XRCC5 was validated using dual-luciferase reporter assay and RIP assay. Xenograft models were constructed to uncover the effect of RUSC1-AS1 on BC tumorigenesis. RUSC1-AS1 was upregulated in BC, and its downregulation suppressed BC proliferation, metastasis, cell cycle, angiogenesis, and tumor growth. MiR-326 was confirmed to be sponged by RUSC1-AS1, and its inhibitor reversed the regulation of RUSC1-AS1 silencing on BC progression. XRCC5 could be targeted by miR-326. Overexpression of XRCC5 reversed the inhibitory impacts of miR-326 on BC progression. RUSC1-AS1 could serve as a sponge of miR-326 to promote BC progression by targeting XRCC5, suggesting that RUSC1-AS1 might be a target for BC treatment.

PAX5-miR-142 feedback loop promotes breast cancer proliferation by regulating DNMT1 and ZEB1

BackgroundBreast cancer is one of the most common malignancies occurred in female around the globe. Recent studies have revealed the crucial characters of miRNA and genes, as well as the essential roles of epigenetic regulation in breast cancer initiation and progression. In our previous study, miR-142-3p was identified as a tumor suppressor and led to G2/M arrest through targeting CDC25C. However, the specific mechanism is still uncertain.MethodsWe identified PAX5 as the upstream regulator of miR-142-5p/3p through ALGGEN website and verified by series of assays in vitro and in vivo. The expression of PAX5 in breast cancer was detected by qRT-PCR and western blot. Besides, bioinformatics analysis and BSP sequencing were performed to analyze the methylation of PAX5 promoter region. Finally, the binding sites of miR-142 on DNMT1 and ZEB1 were predicted by JASPAR, and proved by luciferase reporter assay, ChIP analysis and co-IP.ResultsPAX5 functioned as a tumor suppressor by positive regulation of miR-142-5p/3p both in vitro and in vivo. The expression of PAX5 was regulated by the methylation of its promoter region induced by DNMT1 and ZEB1. In addition, miR-142-5p/3p could regulate the expression of DNMT1 and ZEB1 through binding with their 3’UTR region, respectively.ConclusionIn summary, PAX5-miR-142-DNMT1/ZEB1 constructed a negative feedback loop to regulate the progression of breast cancer, which provided emerging strategies for breast cancer therapy.

NNAT is a novel mediator of oxidative stress that suppresses ER + breast cancer

BackgroundNeuronatin (NNAT) was recently identified as a novel mediator of estrogen receptor-positive (ER+) breast cancer cell proliferation and migration, which correlated with decreased tumorigenic potential and prolonged patient survival. However, despite these observations, the molecular and pathophysiological role(s) of NNAT in ER + breast cancer remains unclear. Based on high protein homology with phospholamban, we hypothesized that NNAT mediates the homeostasis of intracellular calcium [Ca2+]i levels and endoplasmic reticulum (EndoR) function, which is frequently disrupted in ER + breast cancer and other malignancies.MethodsTo evaluate the role of NNAT on [Ca2+]i homeostasis, we used a combination of bioinformatics, gene expression and promoter activity assays, CRISPR gene manipulation, pharmacological tools and confocal imaging to characterize the association between ROS, NNAT and calcium signaling.ResultsOur data indicate that NNAT localizes predominantly to EndoR and lysosome, and genetic manipulation of NNAT levels demonstrated that NNAT modulates [Ca2+]i influx and maintains Ca2+ homeostasis. Pharmacological inhibition of calcium channels revealed that NNAT regulates [Ca2+]i levels in breast cancer cells through the interaction with ORAI but not the TRPC signaling cascade. Furthermore, NNAT is transcriptionally regulated by NRF1, PPARα, and PPARγ and is strongly upregulated by oxidative stress via the ROS and PPAR signaling cascades.ConclusionCollectively, these data suggest that NNAT expression is mediated by oxidative stress and acts as a regulator of Ca2+ homeostasis to impact ER + breast cancer proliferation, thus providing a molecular link between the longstanding observation that is accumulating ROS and altered Ca2+ signaling are key oncogenic drivers of cancer.

Fractions of Methanol Extracts from the Resurrection Plant Haberlea rhodopensis Have Anti-Breast Cancer Effects in Model Cell Systems

Breast cancer is among the most problematic diseases and a leading cause of death in women. The methods of therapy widely used, so far, are often with many side effects, seriously hampering patients’ quality of life. To overcome these constraints, new cancer treatment alternatives are constantly tested, including bioactive compounds of plant origin. Our aim was to study the effects of Haberlea rhodopensis methanol extract fractions on cell viability and proliferation of two model breast cancer cell lines with different characteristics. In addition to the strong reduction in cell viability, two of the fractions showed significant influence on the proliferation rate of the hormone receptor expressing MCF7 and the triple negative MDA-MB231 breast cancer cell lines. No significant effects on the benign MCF10A cell line were observed. We applied a large scale non-targeted approach to purify and identify highly abundant compounds from the active fractions of H. rhodopensis extracts. By the combined NMR/MS approach, myconoside was identified in the fractions and hispidulin 8-C-(6-O-acetyl-2″-O-syringoyl-β-glucopyranoside) was found in one of them. We further performed molecular docking analysis of possible myconoside interactions with several proteins, important for breast cancer proliferation. High probability of binding was established for GLUT1 transporter, estrogen receptor and MYST acetyltransferase. Our results are a good background for future studies on the use of myconoside for targeted breast cancer therapy.

Green Synthesised TiO2 Nanoparticles-Mediated Terenna asiatica: Evaluation of Their Role in Reducing Oxidative Stress, Inflammation and Human Breast Cancer Proliferation.

Oxidative stress and chronic inflammation interplay with the pathogenesis of cancer. Breast cancer in women is the burning issue of this century, despite chemotherapy and magnetic therapy. The management of secondary complications triggered by post-chemotherapy poses a great challenge. Thus, identifying target-specific drugs with anticancer potential without secondary complications is a challenging task for the scientific community. It is possible that green technology has been employed in a greater way in order to fabricate nanoparticles by amalgamating plants with medicinal potential with metal oxide nanoparticles that impart high therapeutic properties with the least toxicity. Thus, the present study describes the synthesis of Titanium dioxide nanoparticles (TiO2 NPs) using aqueous Terenna asiatica fruit extract, with its antioxidant, anti-inflammatory and anticancer properties. The characterisation of TiO2 NPs was carried out using a powdered X-ray diffractometer (XRD), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), energy-dispersive X-ray diffraction (EDX), high-resolution transmission electron microscopy (HR-TEM), dynamic light scattering (DLS), and zeta-potential. TiO2 NPs showed their antioxidant property by scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radicals in a dose-dependent manner with an IC50 value of 80.21 µg/µL. To ascertain the observed antioxidant potential of TiO2 NPs, red blood cells (RBC) were used as an in vitro model system. Interestingly, TiO2 NPs significantly ameliorated all the stress parameters, such as lipid peroxidation (LPO), protein carbonyl content (PCC), total thiol (TT), superoxide dismutase (SOD), and catalase (CAT) in sodium nitrite (NaNO2)-induced oxidative stress, in RBC. Furthermore, TiO2 NPs inhibited RBC membrane lysis and the denaturation of both egg and bovine serum albumin, significantly in a dose-dependent manner, suggesting its anti-inflammatory property. Interestingly, TiO2 NPs were found to kill the MCF-7 cells as a significant decrease in cell viability of the MCF-7 cell lines was observed. The percentage of growth inhibition of the MCF-7 cells was compared to that of untreated cells at various doses (12.5, 25, 50, 100, and 200 µg/mL). The IC50 value of TiO2 NPs was found to be (120 µg/mL). Furthermore, the Annexin V/PI staining test was carried out to confirm apoptosis. The assay indicated apoptosis in cancer cells after 24 h of exposure to TiO2 NPs (120 µg/mL). The untreated cells showed no significant apoptosis in comparison with the standard drug doxorubicin. In conclusion, TiO2 NPs potentially ameliorate NaNO2-induced oxidative stress in RBC, inflammation and MCF-7 cells proliferation.

Multifaceted Networking of The Orphan Receptor Estrogen-Related Receptor Β in Breast Cancer Progression

Breast cancer death polls are rising at an alarming rate in females globally. It is a hormone-dependent disease that is majorly regulated by estrogen. Several genetic and environmental factors are the primary attributes of breast cancer growth and development. A higher proportion of breast cancer patients harbor estrogen receptor-positive (ER+ve) status. Estrogen related receptors are orphan nuclear receptors which include ERRα, ERRβ, and ERRϒ that exhibit a sequence similarity with ERα. ERRα and ERRϒ act as activators in cancer. ERRβ expression is downregulated in breast cancer cells and patient samples, compared to healthy breast cells. The decreased expression of ERRβ is primarily mediated by the proteasomal pathway at the protein level. ERRβ restricts cell cycle progression in breast cancer cells, thereby impeding breast cancer proliferation. Neddylation of ERRβ mediates its downregulation which triggers the oncogenic signalling in breast cancer. Our study showed employing MLN4924, an NAE inhibitor to restore the expressivity of ERRβ could provide a successful and cutting-edge therapeutic method. This review article illustrates the regulatory role of ERRβ in the formation and evolution of breast cancer, making it an effective therapeutic candidate.

Role of Nudt2 in Anchorage-Independent Growth and Cell Migration of Human Melanoma.

Nudt2 encodes a diadenosine tetraphosphate (Ap4A) hydrolase that catalyzes the hydrolysis of Ap4A and is involved in the lysyl tRNA synthetase-Ap4A-Nudt2 (LysRS-Ap4A-Nudt2) signaling pathway. We have previously demonstrated that this pathway is active in non-small cell lung cancer. Nudt2 was shown to be involved in cell proliferation in breast cancer, making it an important target in cancer therapy. Currently, the function of Nudt2 in malignant melanoma has not been demonstrated. Therefore, we investigated the role played by Nudt2 in the growth of human melanoma. Our study showed that Nudt2 knockdown suppressed anchorage-independent growth of human melanoma cells in vitro. The in vivo effect of Nudt2 was determined by investigating the role played by Nudt2 knockdown on the ability of the cells to form tumors in a mice xenograft model. Nudt2 knockdown significantly suppressed tumor growth in this model. Moreover, overexpression of Nudt2 resulted in an increase in anchorage-independent growth of these cells, whereas Nudt2 knockdown decreased their migration. In addition, Nudt2 knockdown reduced vimentin expression. Vimentin is one of the mesenchymal markers that are involved in the epithelial mesenchymal transition (EMT) process. Thus, Nudt2 plays an important role in promoting anchorage-independent growth and cell migration in melanoma.