Inhibited MCF-7 Breast Cancer Cell Research Articles

Mechanism of ergosterol peroxide on MCF-7 breast cancer cells based on network pharmacology and in vitro experiments

This study investigated the effects of ergosterol peroxide(EP) on the proliferation and apoptosis of MCF-7 breast cancer cells, explored its possible mechanisms of action, and verified the effects and mechanisms by in vitro experiments. Network pharmaco-logy was used to screen the target proteins of EP and construct target networks and protein-protein interaction(PPI) networks to predict the potential target proteins and related pathways involved in EP anti-breast cancer effects. The MTT assay was performed to measure the inhibitory effect of EP on MCF-7 cell proliferation, and the colony formation assay was used to assess the cell cloning ability. Flow cytometry and laser confocal microscopy were employed to evaluate cell apoptosis, mitochondrial membrane potential and reactive oxygen species(ROS) levels. Western blot analysis was conducted to examine the expression levels of B-cell lymphoma 2(Bcl-2), Bcl-2-associated X protein(Bax), cytochrome C(Cyt C), caspase-7, cleaved caspase-7, phosphatidylinositol 3-kinase(PI3K), and se-rine/threonine kinase B(AKT) in MCF-7 cells treated with EP. The results of network pharmacology prediction yielded 173 common targets between EP and breast cancer; the results of Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis showed that EP treatment for breast cancer mainly affected the signaling pathways such as cancer pathway, PI3K-AKT signaling pathway, cellular senescence signaling pathway, and viral carcinogenesis pathway; and the MTT assay results showed that the viability of MCF-7 cells in the EP group was significantly lower than that in the control group, exhibiting a time-and concentration-dependent trend, and EP can inhibit colony formation of MCF-7 breast cancer cells. Treatment with 10, 20, and 40 μmol·L~(-1) EP for 24 h resulted in a significant increase in the total apoptosis rate of MCF-7 cells, a significant decrease in mitochondrial membrane potential, and a significant increase in ROS levels. In addition, treatment with EP led to an upregulation of Cyt C, Bax, and cleaved caspase-7 protein expression, and a downregulation of p-PI3K, p-AKT, and Bcl-2 protein expression in MCF-7 cells. Studies have shown that EP inhibits MCF-7 breast cancer cell proliferation and reduces colony formation by a mechanism that may be related to the PI3K-AKT pathway mediating the mitochondrial apoptotic pathway.

Insulin-like growth factor binding protein-3 induces senescence by inhibiting telomerase activity in MCF-7 breast cancer cells

Insulin-like growth factor binding protein-3 (IGFBP-3) has been known to inhibit cell proliferation and exert tumor-suppressing effects depending on the cell type. In this study, we aimed to show that IGFBP-3 induces cellular senescence via suppression of the telomerase activity, thereby inhibiting MCF-7 breast cancer cell proliferation. We found that the induction of IGFBP-3 in MCF-7 cells enhanced the loss of cell viability. Flow cytometry revealed a higher percentage of non-cycling cells among IGFBP-3-expressing cells than among controls. IGFBP-3 induction also resulted in morphological alterations, such as a flattened cytoplasm and increased granularity, suggesting that IGFBP-3 induces a senescence-like phenotype. The percentage of IGFBP-3 expressing cells with senescence-associated β-galactosidase activity was 3.4 times higher than control cells. Telomeric repeat amplification and real-time PCR showed that IGFBP-3 decreased telomerase activity by reducing the levels of the RNA component (hTR) and catalytic protein component with reverse transcriptase activity (hTERT) of telomerase in a dose-dependent manner. These results suggest that IGFBP-3 is a negative regulator of MCF-7 breast cancer cell growth by inducing senescence through telomerase suppression.

Peimine Inhibits MCF-7 Breast Cancer Cell Growth by Modulating Inflammasome Activation: Critical Roles of MAPK and NF-κB Signaling.

Peimine (PM) is a bioactive compound obtained from Fritillaria. It has been documented that PM exhibits potent antitumor properties against multiple cancers. However, the antitumor properties of PM in breast cancer and its associated mechanisms have not been clarified. Proliferation and apoptosis of MCF-7 and MCF-10A cells were detected by CCK8, colony formation, and flow cytometry assays. Cytotoxicity was measured by Lactate dehydrogenase (LDH) leakage assay. The level of IL-1β and IL-18 were detected with ELISA kits. Western blotting and real-time Polymerase Chain Reaction were performed to analyze the expression of proteins and genes related to the NLRP3 inflammasome pathway and Endoplasmic reticulum stress. The doses of PM (5, 10, and 20 μM) inhibited cell viability significantly, apoptotic induction, and inflammasome activation in breast cancer cells in vitro. Inflammasome components were decreased, including the apoptosisassociated speck like protein containing a CARD (ASC) and NOD-like receptor pyrindomain-containing protein3 (NLRP3), as well as the inhibition of caspase-1 and interleukin-1β activation. Moreover, inflammasome inhibitors suppressed cell growth and induced apoptosis, implying that PM suppresses the growth of breast cancer cells through regulating inflammasome. Mechanistically, PM inhibited the activity of inflammasome by alleviating endoplasmic reticulum (ER) stress and by down-regulating the expression of multiple proteins in transcription factor nuclear factor- κB (NF-κB) and mitogen-activated protein kinases (MAPKs) signaling pathways. These findings show that PM suppresses the growth of breast cancer cells by inhibiting inflammasome activation, to a certain extent, by primarily acting on the MAPK/NF-κB pathway's inactivation-dependent mechanisms.

Beta-sitosterol from sablo ( Acalypha wilkesiana Muell. Arg.) leaves induce apoptosis in MCF-7 Breast cancer cell lines

One of the most common malignancy breast cancer is highly prevalent among women. Based on the natural ingredients it contains, the plants of sablo have the potential to be employed as an anticancer therapeutic. Numerous studies have demonstrated that the chance of developing breast cancer rises with age. Additionally, the prevalence of breast cancer varies according to the different types of biased traditional Chinese medicine constitution, and the Qi-depressed constitution is highly concomitant and increases the prevalence of breast cancer. As a result, the Qi-depressed constitution is a separate risk factor for breast cancer. Previous studies have shown that the ethanol extract of Acalypha wilkesiana and its components have potential as anticancer agent against MCF-7. In the current study, using resazurin assays and flow cytometry, beta-sitosterol extracted from Acalypha wilkesiana was examined in MCF-7 human breast cancer cell lines. Resazurin experiments demonstrated its capacity to inhibit cell proliferation and trigger apoptosis, and flow cytometry was utilized to examine this capacity. Beta-sitosterol inhibits MCF-7 breast cancer cell proliferation and has an apoptotic activity that is proportional to the dose. The results of this study imply that beta-sitosterol may be used to treat cancer.

The combined restoration of miR-424-5p and miR-142-3p effectively inhibits MCF-7 breast cancer cell line via modulating apoptosis, proliferation, colony formation, cell cycle and autophagy.

The combined restoration of tumor-suppressive microRNAs (miRs) has been identified as a promising approach for inhibiting breast cancer development. This study investigated the effect of the combined restoration of miR-424-5p and miR-142-3p on MCF-7 cells and compared the efficacy of the combined therapy with the monotherapies with miR-424-5p and miR-142-3p. After transfection of miR-424-5p and miR-142-3p mimics into MCF-7 cells in the combined and separated manner, the proliferation of tumoral cells was assessed by the MTT assay. Also, the apoptosis, autophagy, and cell cycle of the cells were analyzed by flow cytometry. Western blot and qRT-PCR were used to study the expression levels of c-Myc, Bcl-2, Bax, STAT-3, Oct-3, and Beclin-1. Our results have demonstrated that the combined restoration of miR-424-5p and miR-142-3p is more effective in inhibiting tumor proliferation via upregulating Bax and Beclin-1 and downregulating Bcl-2 and c-Myc. Besides, the combined therapy has arrested the cell cycle in the sub-G1 and G2 phases and has suppressed the clonogenicity via downregulating STAT-3 and Oct-3, respectively. The combined restoration of miR-424-5p and miR-142-3p is more effective in inhibiting MCF-7 breast cancer development than monotherapies with miR-424-5p and miR-142-3p.

LC-MS/MS and Cytotoxic Activity Analysis of Extract and Fraction of Calophyllum soulattri Stembark

Calophyllum soulattri (Sulatri), a plant from Clusiaceae family, has been empirically used as traditional medicine. In the present study, C. soulattri stem bark extract and fractions were evaluated for their toxicity against MCF-7 breast cancer cell. The extract and fraction’s chemical content was analyzed using the combination of liquid chromatography with mass spectrometry (LC-MS/MS). The results showed that methanol extract and n-hexane fractions have strong cytotoxic activity with IC50 values 93.6 and 36 µg/mL, respectively. Meanwhile, as the positive control, ethyl acetate and cisplatin fractions have IC50 values 233 and 16.2 µg/mL, respectively. The LC-MS/MS analysis showed that the extract and fractions contained polyporusterone A, poricoic acid D, polyporusterone F, esulentagenin, and 1-acetyl-3-(methoxy-carbonyl)-β-carboline. Therefore, C. soulattri stem bark extract and fractions have potential activity as an anticancer agent that was able to inhibit MCF-7 breast cancer cell growth.

In vitro studies on inhibition capability of fungal-sourced bassiatin versus tamoxifen against ERα, EGFR and VEGFR on breast cancer cells.

Bassiatin which is produced by some fungi, is morpholine-based depsipeptide. Recent studies show that bassiatin inhibits MCF-7 breast cancer cell proliferation with its anti-oestrogenic effect. In this study, bassiatin's inhibition versus Tamoxifen was examined by comparing the effects on epidermal growth factor receptor and vascular endothelial growth factor receptor in addition to oestrogen receptor on breast cells. For this purpose, 15 concentrations of bassiatin, tamoxifen and combination of both were treated in terms of cytotoxicity on MCF-7, MDA-MB-231, SK-BR-3 and SVCT cell lines. For cell cycle analyses, MCF-7 and SVCT cell lines were incubated with 37.5 μM bassiatin, tamoxifen and combined substance for 24 h and 48 h. After treatment, cell distribution in each phase of the cell cycle was measured with flow cytometer. Furthermore, each interaction related to receptors were investigated with immunoassay ELISA kits. As a result, bassiatin-induced MCF-7 cell cycle arrest was shown in G0/G1 and G2/M phases at the presence of bassiatin. It was also found that bassiatin is more effective at all examined receptors on breast cancer cells than tamoxifen. These results show that bassiatin can be used effectively in breast cancer treatment as a new anticancer agent because of its multiple inhibition effects.

Novel pyrazolo[4,3-d]pyrimidine microtubule targeting agents (MTAs): Synthesis, structure–activity relationship, in vitro and in vivo evaluation as antitumor agents

The design, synthesis, and biological evaluation of a series novel N1‑methyl pyrazolo[4,3-d]pyrimidines as inhibitors of tubulin polymerization and colchicine binding were described here. Synthesis of target compounds involved alkylation of the pyrazolo scaffold, which afforded two regioisomers. These were separated, characterized and identified with 1H NMR and NOESY spectroscopy. All compounds, except 10, inhibited [3H]colchicine binding to tubulin, and the potent inhibition was similar to that obtained with CA-4. Compounds 9 and 11–13 strongly inhibited the polymerization of tubulin, with IC50 values of 0.45, 0.42, 0.49 and 0.42 μM, respectively. Compounds 14–16 inhibited the polymerization of tubulin with IC50s near ∼1 μM. Compounds 9, 12, 13 and 16 inhibited MCF-7 breast cancer cell lines and circumvented βIII-tubulin mediated cancer cell resistance to taxanes and other MTAs, and compounds 9–17 circumvented Pgp-mediated drug resistance. In the standard NCI testing protocol, compound 9 exhibited excellent potency with low to sub nanomolar GI50 values (≤10 nM) against most tumor cell lines, including several multidrug resistant phenotypes. Compound 9 was significantly (P < 0.0001) better than paclitaxel at reducing MCF-7 TUBB3 (βIII-tubulin overexpressing) tumors in a mouse xenograft model. Collectively, these studies support the further preclinical development of the pyrazolo[4,3-d]pyrimidine scaffold as a new generation of tubulin inhibitors and 9 as an anticancer agent with advantages over paclitaxel.

GSF3, a polysaccharide from guava (Psidium guajava L.) seeds, inhibits MCF-7 breast cancer cell growth via increasing Bax/Bcl-2 ratio or Fas mRNA expression levels

Guava seed polysaccharide fraction 3 (GSF3) is an immunomodulatory polysaccharide from guava (Psidium guajava L.) seed polysaccharides. However, effects of GSF3 on the growth of breast cancer cells were not understood, yet. To clarify the GSF3 effects on breast cancer cell growth, GSF3 was subjected to treat MCF-7 cells using direct action or indirect immunotherapy using immune cells conditioned media, respectively. The viabilities of MCF-7 cells were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Changes in pro-(Bax)/anti-apoptotic (Bcl-2) and Fas mRNA expression levels in the treated MCF-7 cells were measured using two-step reverse transcription quantitative polymerase chain reaction. Our results showed that GSF3 inhibited MCF-7 cell growth through either direct action or indirect immunotherapy. GSF3 direct action significantly (P < 0.05) decreased Bcl-2 mRNA expression amount but increased pro-(Bax)/anti-apoptotic (Bcl-2) mRNA expression ratios in the treated cells. The splenocytes conditioned media cultured with GSF3 increased Fas mRNA expression amounts in the treated MCF-7 cells. There was a significant negative correlation between Th2-polarized cytokines secreted by immune cells and Fas mRNA expression levels in the corresponding treated MCF-7 cells. Our findings suggested that GSF3 is a potent anti-cancerous polysaccharide by direct action or indirectly modulating immune cell cytokine secretion profiles.

Identification of hub genes and potential molecular mechanisms of chickpea isoflavones on MCF-7 breast cancer cells by integrated bioinformatics analysis.

Chickpea isoflavones have been demonstrated to play an inhibitory role in breast cancer cells. In this study, we aimed to explore the mechanism of chickpea isoflavones inhibiting the formation and development of breast carcinoma through the integration of wet and dry experiments. Chickpea isoflavones were added to the MCF-7 cells for 48 hours, and the subsequent morphological changes of cells were observed using an inverted microscope, while apoptosis was quantified by flow cytometry. The mRNA and LncRNA expression profiles were detected by RNA-sequencing (RNA-Seq) technology. The protein-protein interaction (PPI) network was constructed from the STRINGdb database. To identify the co-expressed long non-coding RNA and messenger RNA (lncRNA-mRNA) pairs, Pearson's correlation coefficients were calculated based on the expression value between every differentially expressed lncRNA and mRNA pair. The hub gene expression was verified by quantitative reverse transcription polymerase chain reaction (qRT-PCR), and survival analysis results were provided by The Human Protein Atlas website. Microscopic observation and flow cytometry results confirmed that chickpea isoflavones with a final concentration of 32.8 µg/mL could cause apoptosis of the MCF-7 cells. Transcriptome results showed that a total of 1,094 mRNAs and 378 lncRNAs were differentially expressed in isoflavone-treated cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment revealed that inhibition of cell proliferation was mainly due to the up-regulation of genes in the apoptosis signaling pathway and the down-regulation of genes in mRNA splicing pathway. The co-expressed genes of the top 10 down-regulated lncRNAs were mainly heterogeneous nuclear ribonucleoproteins (HNRNP) family genes, which interacted with apoptosis-related genes through ubiquitin C (UBC). The abnormal expression of 11 hub genes (degree >10) of PPI networks were beneficial to improve the overall survival time of breast cancer patients. Our results reveal a potential mechanism for chickpea isoflavones to inhibit MCF-7 breast cancer cell proliferation and provide a reference for the development of new anti-cancer drugs used in breast cancer.

AgNPs loaded microemulsion using gallic acid inhibits MCF-7 breast cancer cell line and solid ehrlich carcinoma

The objective of this present work is to optimize and prepare silver nanoparticles(AgNPs) in Dioctyl sodium sulfosuccinate (AOT) microemulsion (ME) for oral use and to investigate its antibacterial and anticancer activity in vitro and in vivo. In vitro drug release study confirmed that faster release of drug at the tumor cells compared to the blood circulation. It also showed a potential antibacterial activity against pathogenic bacteria. The optimized AgNPs loaded ME confirmed significant cytotoxicity against MCF-7 cancer cell line with IC50 16.72 ± 0.014 μg/mL and significant reduction in solid Ehrlich tumor growth in compared to the control, placebo and pure drug.

Enhanced chemotherapeutic efficacy of the low-dose doxorubicin in breast cancer via nanoparticle delivery system crosslinked hyaluronic acid

Despite the development of treatment options in breast cancer, many patients die of recurrence and metastasis. Owing to enhanced permeability and retention in solid tumor tissue, nanoparticle (NP) delivery systems have been emerged as novel strategy in cancer chemotherapy. As extracellular matrix, glycosaminoglycan hyaluronan (HA) could bind its surface receptor adhesion molecule CD44 which is strongly expressed on breast cancer. We have previously reported a doxorubicin (DOX)-loaded HA-Lys-LA X-NPs (X-NP-DOX) NP delivery system for breast cancer treatment. In this study, we further investigated the antitumor effect of X-NP-DOX NP delivery system using low-dose DOX in both in vitro and in vivo systems. We demonstrated that low-dose X-NP-DOX possessed the ability for inhibiting MCF-7 breast cancer cell growth, invasion, and migration, and inducing apoptosis in vitro. In in vivo experiments, injection of low-dose X-NP-DOX into tumor-bearing mouse resulted in significant reduction of tumor size. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining further revealed that low-dose X-NP-DOX induced higher percentage of apoptotic cells compared with free DOX or saline. Furthermore, our study demonstrated that low-dose X-NP-DOX inhibited Notch1 and Ras/MAPK pathways, decreased cancer stem cell population, and reduced tumorigenesis compared to free DOX in both in vitro and in vivo settings. Owing to its enhanced efficacy and higher targetability compared to free DOX, low-dose DOX delivered by NP system may be a promising novel strategy for breast cancer treatment.

New Class of Selective Estrogen Receptor Degraders (SERDs): Expanding the Toolbox of PROTAC Degrons.

An effective endocrine therapy for breast cancer is to selectively and effectively degrade the estrogen receptor (ER). Up until now, there have been largely only two molecular scaffolds capable of doing this. In this study, we have developed new classes of scaffolds that possess selective estrogen receptor degrader (SERD) and ER antagonistic properties. These novel SERDs potently inhibit MCF-7 breast cancer cell proliferation and the expression of ER target genes, and their efficacy is comparable to Fulvestrant. Unlike Fulvestrant, the modular protein-targeted chimera (PROTAC)-type design of these novel SERDs should allow easy diversification into a library of analogs to further fine-tune their pharmacokinetic properties including oral availability. This work also expands the pool of currently available PROTAC-type scaffolds that could be beneficial for targeted degradation of various other therapeutically important proteins.

Methyl elaidate: A major compound of potential anticancer extract of Moringa oleifera seeds binds with bax and MDM2 (p53 inhibitor) In silico

Background: Apoptosis is an energy-required programmed cell death process that is vital for normal homeostasis. This is because aged, malfunctioning, and genetically deficient cells such as cancer cells are eliminated through this process to avoid any abnormality in the function of the body system. Earlier, we have reported that the Lipophilic hexane fraction of crude ethanolic extract (HF-CEE) of Moringa oleifera seeds inhibited MCF7 breast cancer cell growth. Objectives: The aims of this study are to identify the esters responsible for HF-CEE cytotoxicity and to determine the ability of the compound to trigger Bax and p53 apoptotic proteins. Materials and Methods: Gas chromatography–mass spectrometry (GC-MS) analysis of the HF-CEE was performed. Methyl elaidate, the major compound identified, was molecularly docked with Bax and MDM2 (p53 inhibitor) using AutoDock 4.2. Drug suitability of methyl elaidate was determined by the rule of “5.” Results: Eleven different esters were identified in HF-CEE by GC-MS. Methyl elaidate was the major anticancer agent among the esters. Methyl elaidate bound with Bax and MDM2 at their active sites that can trigger apoptosis in cancer cells. Finally, methyl elaidate has potential drug properties according to the rule of “5.” Conclusion: Methyl elaidate of HF-CEE could be responsible for its anticancer activity and it is a potential apoptotic agent. Abbreviations used: HF-CEE: Hexane fraction of crude ethanolic extract of Moringa oleifera seeds; GC-MS: Gas chromatography mass spectrometry; MDM2: Mouse double minute 2 homolog.

Interaction of antihistaminic drugs with human translationally controlled tumor protein (TCTP) as novel approach for differentiation therapy.

Translationally controlled tumor protein (TCTP) represents an exquisite target for cancer differentiation therapy, because it was most strikingly down-regulated in tumor reversion experiments. Since TCTP is identical with the histamine releasing factor, antihistamic drugs may inhibit TCTP. Indeed, antihistaminics, such as promethazine, thioridazine, perphemazine and chlorpromazine reveal antiproliferative effects. The aim of this investigation was to study antihistaminic drugs as new TCTP inhibitors to inhibit tumor growth. Levomepromazine and buclizine showed higher in silico binding affinities to TCTP among 12 different antihistaminic compounds including the control drugs, promethazine and hydroxyzine by using Autodock4 and AutodockTools-1.5.7.rc1. Recombinant human TCTP was codon-optimized, expressed in E. coli and purified by chitin affinity chromatography. For experimental validation of in silico data, we applied microscale thermophoresis. Levomepromazine bound with a Kd of 57.2 μM (p < 0.01) and buclizine with a Kd of 433μM (p < 0.01) to recombinant TCTP. Both drugs inhibited MCF-7 breast cancer cell growth in resazurin assays. TCTP expression was down-regulated after treatment with the two drugs. Cell cycle was arrested in the G1 phase without apoptosis as confirmed by the expression of cell cycle and apoptosis-regulating proteins. Annexin V-PI staining and Trypan blue exclusion assay supported that the two drugs are cytostatic rather than cytotoxic. Induction of differentiation with two drugs was detected by the increased appearance of lipid droplets. In conclusion, levomepromazine and buclizine inhibited cancer cell growth by binding to TCTP and induction of cell differentiation. These compounds may serve as lead compounds for cancer differentiation therapy.

Retinal-conjugated pH-sensitive micelles induce tumor senescence for boosting breast cancer chemotherapy

Evoking tumor cellular senescence, an irreversible status of cell growth quiescence, has been recently proposed as a potential strategy to improve the efficacy of cancer treatment. In the current study, all-trans retinal, the precursor of all-trans retinoic acid, was conjugated to dextran via hydrazone bond to generate amphiphilic dextran-retinal (DR) conjugates, which self-assembled into pH-sensitive DR micelles. Our results showed that DR micelles moderately inhibited MCF-7 breast cancer cell growth through inducing p21-associated cellular senescence, which relied on retinoic acid receptors (RARs) and was accompanied by significant G0/G1 cell cycle arrest. Moreover, DR micelles were capable of encapsulating doxorubicin (DOX) to generate DOX-loaded DD micelles, facilitating the uptake and release of DOX in cancer cells. Compared with free DOX, DD micelles more effectively suppressed tumor growth and prolonged survival time of mouse xenograft model through inducing tumor apoptosis and cellular senescence. However, blocking cellular senescence diminished DD-caused apoptosis in MCF-7 cells by 40–50%. Therefore, pH-sensitive DR micelles not only served as a potent platform for DOX delivery, but also enhanced the anti-tumor effect of DOX by inducing tumor cellular senescence. These data reveal a great potential of evoking tumor senescence with retinal-conjugated micelles for boosting breast cancer chemotherapy.

Abstract 2723: Breast cancer type 1 susceptibility protein mimetics induce specific estrogen receptor confirmations and inhibit MCF7 breast cancer cell proliferation

Abstract The human Estrogen Receptor (hER) is present in 70% of breast cancers, and dysregulation of hER signaling can lead to aberrant cell growth and proliferation. Known anti-estrogens used in treatments of breast cancer today, tamoxifen and raloxifene cause hER to undergo conformational changes and inhibit normal hER signaling by directly binding to the ligand binding pocket. However, often breast cancer cells become resistant to tamoxifen, and prolonged tamoxifen treatment can lead to endometrial cancers. Breast Cancer Type 1 Susceptibility protein (BRCA1) is a well characterized inhibitor of breast cancer cell growth. BRCA1 plays an important role in maintaining genomic stability through various DNA repair mechanisms. It is mutated in approximately 50% of breast cancer cases that are associated with heredity. While the majority of breast cancer cases are “sporadic” or unassociated with heredity, BRCA1 is expressed 30 to 40 % less in sporadic breast cancers. BRCA1 has also been shown to associate directly with hER, and inhibit transactivation of hER. This association and inhibition of hER transcriptional activity is reversed by cyclin D1. This, in conjunction with studies that have shown that cyclin D1 gene and protein levels are amplified and overexpressed respectively in breast cancers suggest that the normal regulation of hER by BRCA1 and cyclin D1 may be shifted in breast cancers to primarily regulation (activation) by cyclin D1 and other coactivators. A decrease in BRCA1 is associated with acquired tamoxifen resistance, suggesting that BRCA1 may play a critical role in maintaining breast cancer cells sensitivity to tamoxifen. The hER binding region of BRCA1 contains the known corepressor binding motif LXXIIXXXL (amino acids 78-95). Here we present a study of several small molecules identified based on pharmacophoric features of previously found conformation sensing BRCA1 peptides. BRCA1 mimetics induce unique ER conformations and inhibit breast cancer cell growth (MCF7). Further development of these compounds could lead to viable alternative breast cancer treatments as well as supplemental treatments in the anti-estrogen resistant cases. Acknowledgements: This research was supported via funds from the New York State, National Institutes of Health (5P20MD002725), through the NCMHD -RIMI program (RVR) and NSF LSAMP Bridge to Doctorate grant (BKA). Citation Format: Bethany Kristen Asare, Christ Ange Katche, Rajendram V. Rajnarayanan. Breast cancer type 1 susceptibility protein mimetics induce specific estrogen receptor confirmations and inhibit MCF7 breast cancer cell proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2723. doi:10.1158/1538-7445.AM2014-2723

Inhibition of breast cancer cell proliferation through disturbance of the calcineurin/NFAT pathway by human herpesvirus 6B U54 tegument protein.

Nuclear factor of activated T cell (NFAT) proteins are key regulators involved in multiple physiological mechanisms, such as immune response and cell growth. The capacity of selective calcineurin/NFAT inhibitors to decrease NFAT-dependent cancer cell progression, particularly in breast cancer, has already been demonstrated. In this study, we report a role for the human herpesvirus 6B (HHV-6B) U54 tegument protein in inhibiting MCF-7 breast cancer cell proliferation by inhibiting NFAT activation.

Effect of cycloxygenase-2 silencing on the malignant biological behavior of MCF-7 breast cancer cells.

The aim of the present study was to investigate the effect of cyclooxygenase-2 (COX-2) silencing on the malignant biological behavior of MCF-7 breast cancer cells. COX-2 short hairpin RNA (shRNA) and unassociated sequences were synthesized and a shRNA lentiviral vector was constructed. The vector was transfected into MCF-7 breast cancer cells, in which clones with stable expression were screened out. The expression of COX-2 mRNA and protein was silenced using RNA interference (RNAi). Quantitative polymerase chain reaction, western blotting, a mononuclear cell direct cytotoxicity assay (MTT assay), a cell invasion assay and scratch tests were performed to investigate the downregulation of COX-2 mRNA and protein expression, the proliferative activity and growth rate of MCF-7 breast cancer cells, the glioblastoma multiforme (GBM) penetrating capacity, the cell movement and migratory capacity, and vascular endothelial growth factor (VEGF)-A and VEGF-C protein expression. The results revealed that the sequence-specific shRNA significantly downregulated the expression of COX-2 at the mRNA and protein levels. Furthermore, the downregulation of COX-2 expression markedly decreased the invasive and metastatic capacities of the cells, suppressed the proliferation, decreased the rate of growth, decreased the capacity of GBM penetration and migration, and decreased the protein expression of VEGF-A and VEGF-C, the two key factors that regulate tumor angiogenesis and lymphangiogenesis. In conclusion, the RNAi technique effectively silenced COX-2 gene expression and inhibited MCF-7 breast cancer cell proliferation, invasion and metastasis by decreasing VEGF-A and VEGF-C expression, which regulates tumor angiogenesis and lymphangiogenesis. Therefore, an RNAi technique that targets COX-2 presents a promising prospect for breast cancer gene therapy.

Antioxidant and anticancer activities from leaf extracts of four Combretum species from northern Thailand

Four Combretum species (Combretaceae) from northern Thailand (Combretum deciduum, Combretum griffithii, Combretum latifolium and Combretum quadrangulare) were tested for antioxidant and anticancer activities. Antioxidant activities were assessed by ABTS and DPPH radical scavenging capacity methods. Anticancer activity was tested against three cancerous human cell lines (KB, MCF7 and NCI-H187). All methanolic leaf extracts showed antioxidant activities with the ABTS and DPPH methods. The methanolic leaf extracts of C. deciduum inhibited KB-oral cavity and MCF7-breast cancer cell lines, C. latifolium inhibited MCF7-breast cancer cell line and C. quadrangulare inhibited KB-oral cavity and NCI-H187-small cell lung cancer cell lines. However, the methanolic leaf extracts of C. griffithii were inactive against all three cell lines. All methanolic leaf extracts exhibited non-cytotoxicity to Vero cell lines.