Therapeutic Potential In Breast Cancer Research Articles

Improving therapeutic potential in breast cancer via histone deacetylase inhibitor loaded nanofibrils.

Epigenetic modifications play a significant role in cancer progression, making them potential targets for therapy. Histone deacetylase inhibitors have shown promise in inhibiting cancer cell growth, including in breast cancer (BC). In this research, we examined the potential of using suberoyl anilide hydroxamic acid (SAHA)-loaded β-lg nanofibrils as a drug delivery system for triple-negative BC cell lines. We assessed their impact on cell cycle progression, apoptosis, levels of reactive oxygen species, and mitochondrial membrane potential in cancer cells. The combination of SAHA and β-lg nanofibrils demonstrated enhanced efficacy in inhibiting cell growth, inducing cell cycle arrest, and promoting apoptosis (43.78%) compared to SAHA alone (40.09%). Moreover, it effectively targeted cancer cells without promoting drug resistance while using a low concentration of the nanofibrils. These findings underscore the promising potential of nanofibril-based drug delivery systems for BC treatment.

Telmisartan-loaded liposomes: An innovative weapon against breast cancer

This study focuses on the development of a liposomal preparation for the targeted delivery of Telmisartan in the context of breast cancer treatment. Telmisartan, a pharmaceutical agent with potential anticancer properties, has been encapsulated within liposomes, lipid-based vesicles known for their capacity to enhance drug delivery and improve therapeutic outcomes. The formulation and characterization of Telmisartan-loaded liposomes were conducted, evaluating factors such as size, shape, and drug release profiles. The findings demonstrate that the liposomal preparation effectively encapsulates Telmisartan, maintaining its pharmacological properties. The development of such liposomal formulations holds promise for advancing breast cancer therapies, offering the potential for enhanced treatment efficacy and reduced side effects. This research contributes to the ongoing efforts to explore innovative drug delivery strategies in the realm of breast cancer treatment. Breast cancer is a pervasive and challenging malignancy affecting women worldwide. In the quest for more effective and targeted treatment approaches, the development of liposomal preparations for delivering therapeutic agents to breast cancer cells has emerged as a promising avenue. Telmisartan, originally recognized for its antihypertensive properties, has been increasingly investigated for its potential anticancer effects. This study delves into the design and evaluation of a liposomal formulation for Telmisartan, aiming to enhance its therapeutic potential in breast cancer. The formulation process involved the encapsulation of Telmisartan within lipid-based liposomes, which are well-known for their ability to carry a variety of drugs, protect them from degradation, and enhance their selective delivery to tumor cells.

Pharmacological Therapeutic Potential in Breast Cancer through Calcium Influx Pathways

Numerous cellular processes, including the release of neurotransmitters and the contraction of muscles, are largely triggered and regulated by Ca2+ inflow via Ca2+ permeable ion channels. In addition, Ca2+ influx regulates cellular migration and proliferation, two mechanisms linked to cancer. This study focuses on calcium influx in breast cancer cells and discusses how future drugs for breast cancer therapy may be pharmacological modulators of particular Ca2+ influx channels. Certain breast tumors have altered expression of particular calcium permeable ion channels. Such alterations may occasionally be connected to the prognosis and subtype of breast cancer. These days, models both in vivo and in vitro have assisted in identifying particular Ca2+ channels that are crucial for the growth and invasiveness of cancerous breast cells. Nonetheless, additional research is still needed to fully understand several features of Ca2+ influx in breast cancer. These include figuring out the processes behind the changed expression and the best treatment plan to target breast cancer cells via particular Ca2+ channels. In the upcoming ten years, research should concentrate on the function of Ca2+ influx in mechanisms other than the migration and proliferation of breast cancer cells

Visualizing breast cancer research trends in KSA: A bibliometric analysis

ObjectivesBibliometric analysis has emerged as a valuable method for identifying emerging areas in a given research field. Breast carcinoma has maintained a stable rank as the most common cancer affecting women worldwide. This study performed bibliometric profiling to shed light on breast cancer research conducted in KSA over the past two decades and to present the research output in the field of microRNAs (miRNA) in breast cancer in KSA. MethodsThe Web of Science (WoS) and PubMed databases were selected for data retrieval, because of their high coverage, inclusion of high impact journals and easy access to high quality publications. Data retrieval was performed on January 31, 2022. Data were analyzed with Incites from WoS, PubMed and VOSviewer software version 16.1.8. ResultsThe most dynamic institutions, authors and active funding bodies were identified, and output on research in the field of miRNA was assessed. Bibliometric parameters including the number of publications and citation index were analyzed. A total of 3831 publications in the field were identified. A steep increase was observed in breast cancer research. The maximum number of publications was observed in 2021. King Saud University and King Faisal Specialist Hospital & Research Centre funded most of the projects and contributed the most publications. Visible progress was seen in research exploring the diagnostic and prognostic roles of mRNAs and their therapeutic potential in breast cancer. ConclusionBreast cancer research has attracted substantial attention, as reflected by a notable increase in scientific publications over the past two decades in KSA. The bibliometric parameters revealed crucial information regarding research contributions from various institutions and authors. In the field of miRNAs, notable research investment was observed, but a significant lacuna exists. This study provides a reference that may aid oncologists, researchers and policymakers in planning future research.

Sculponeatin A promotes the ETS1-SYVN1 interaction to induce SLC7A11/xCT-dependent ferroptosis in breast cancer

BackgroundE26 transformation specificity-1 (ETS1) is a transcription factor that is overexpressed in breast cancer (BC) and promotes tumor progression. Sculponeatin A (stA), a new diterpenoid extracted from Isodon sculponeatus, has no reported antitumor mechanism. PurposeHere, we explored the antitumor activity of stA in BC and further clarified its mechanism. MethodsFerroptosis was detected by flow cytometric, glutathione, malondialdehyde, and iron determination assays. The effect of stA on the upstream signaling pathway of ferroptosis was detected by Western blot, gene expression, gene alterations and other approaches. The binding of stA and ETS1 was examined through a microscale thermophoresis assay and a drug affinity responsive target stability assay. An in vivo mouse model experiment was performed to evaluate the therapeutic and potential mechanism of stA. ResultsstA exhibits therapeutic potential in BC by inducing SLC7A11/xCT-dependent ferroptosis. stA decreases the expression of ETS1, which is responsible for xCT-dependent ferroptosis in BC. stA inhibits the transcriptional expression of xCT by directly binding to the ETS domain of the ETS1 protein. In addition, stA promotes proteasomal degradation of ETS1 by triggering ubiquitin ligase synoviolin 1 (SYVN1)-mediated ubiquitination. The K318 site of ETS1 mediates ubiquitination of ETS1 by SYVN1. In a mouse model, stA inhibits tumor growth without causing obvious toxicity. ConclusionTaken together, the results confirm that stA promotes the ETS1-SYVN1 interaction to induce ferroptosis in BC mediated by ETS1 degradation. stA is expected to be used in research of candidate drugs for BC and drug design based on ETS1 degradation.

Promising Effects of N-Docosahexaenoyl Ethanolamine in Breast Cancer: Molecular and Cellular Insights.

Unhealthy dietary habits have been identified as a risk factor for the development and progression of cancer. Therefore, adopting a healthy eating pattern is currently recommended to prevent the onset of different types of cancers, including breast carcinoma. In particular, the Mediterranean diet, based on high consumption of omega-3 polyunsaturated fatty acids (N-3 PUFAs), such as those found in cold-water fish and other seafood, nuts, and seeds, is recommended to reduce the incidence of several chronic-degenerative diseases. Indeed, the consumption of N-3 PUFAs, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduced the risk of different types of cancer, including breast cancer. Moreover, they can counteract breast cancer progression and reduce the side effects of chemotherapy in breast cancer survival. Studies have demonstrated that DHA, exhibiting greater antitumor activity than EPA in breast cancer, can be attributed to its direct impact on breast cancer cells and also due to its conversion into various metabolites. N-docosahexaenoyl ethanolamine, DHEA, is the most studied DHA derivative for its therapeutic potential in breast cancer. In this review, we emphasize the significance of dietary habits and the consumption of N-3 polyunsaturated fatty acids, particularly DHA, and we describe the current knowledge on the antitumoral action of DHA and its derivative DHEA in the treatment of breast cancer.

Sodium New Houttuyfonate Induces Apoptosis of Breast Cancer Cells via ROS/PDK1/AKT/GSK3β Axis

Sodium new houttuyfonate (SNH) has been reported to have anti-inflammatory, anti-fungal, and anti-cancer effects. However, few studies have investigated the effect of SNH on breast cancer. The aim of this study was to investigate whether SNH has therapeutic potential for targeting breast cancer. Immunohistochemistry and Western blot analysis were used to examine the expression of proteins, flow cytometry was used to detect cell apoptosis and ROS levels, and transmission electron microscopy was used to observe mitochondria. Differentially expressed genes (DEGs) between breast cancer-related gene expression profiles (GSE139038 and GSE109169) from GEO DataSets were mainly involved in the immune signaling pathway and the apoptotic signaling pathway. According to in vitro experiments, SNH significantly inhibited the proliferation, migration, and invasiveness of MCF-7 (human cells) and CMT-1211 (canine cells) and promoted apoptosis. To explore the reason for the above cellular changes, it was found that SNH induced the excessive production of ROS, resulting in mitochondrial impairment, and then promoted apoptosis by inhibiting the activation of the PDK1-AKT-GSK3β pathway. Tumor growth, as well as lung and liver metastases, were suppressed under SNH treatment in a mouse breast tumor model. SNH significantly inhibited the proliferation and invasiveness of breast cancer cells and may have significant therapeutic potential in breast cancer.

LncRNA BREA2 promotes metastasis by disrupting the WWP2-mediated ubiquitination of Notch1

Notch has been implicated in human cancers and is a putative therapeutic target. However, the regulation of Notch activation in the nucleus remains largely uncharacterized. Therefore, characterizing the detailed mechanisms governing Notch degradation will identify attractive strategies for treating Notch-activated cancers. Here, we report that the long noncoding RNA (lncRNA) BREA2 drives breast cancer metastasis by stabilizing the Notch1 intracellular domain (NICD1). Moreover, we reveal WW domain containing E3 ubiquitin protein ligase 2 (WWP2) as an E3 ligase for NICD1 at K1821 and a suppressor of breast cancer metastasis. Mechanistically, BREA2 impairs WWP2-NICD1 complex formation and in turn stabilizes NICD1, leading to Notch signaling activation and lung metastasis. BREA2 loss sensitizes breast cancer cells to inhibition of Notch signaling and suppresses the growth of breast cancer patient-derived xenograft tumors, highlighting its therapeutic potential in breast cancer. Taken together, these results reveal the lncRNA BREA2 as a putative regulator of Notch signaling and an oncogenic player driving breast cancer metastasis.

Predictive and Prognostic Role of Tumor-Infiltrating Lymphocytes in Patients with Advanced Breast Cancer Treated with Primary Systemic Therapy.

Tumor-infiltrating lymphocytes (TILs) are gaining recognition as an important immunological biomarker with therapeutic potential in breast cancer. In this cohort study conducted on patients with advanced breast cancer treated with primary systemic therapy (PST), the TILs concentration was correlated with response to PST and survival outcomes. Patients with primary breast cancer treated with PST between 2016 and 2020 were included in this study, approved by IEC, and registered on ClinicalTrials.gov (NCT05250336). Tumor core biopsies obtained prior to starting treatment from 489 patients were assessed for the proportion of stromal TILs by standardized method and categorized into low (0-10% immune cells), intermediate (11-59%), and high (≥ 60%) TILs. TIL concentration and complete pathological response (pCR), disease-free survival (DFS), and overall survival (OS) were correlated. Of the 489 patients, 372 matched the eligibility criteria for assessment of TILs and made the final study cohort. Among these, 135 were luminal, 129 HER2-enriched, and 108 triple-negative breast cancers (TNBC). Proportions of patients with high TILs were greater in TNBC (15.7%) and HER2-enriched (9.3%), compared to luminal cancers (4.4%). High TIL concentration was correlated with higher pCR in all subtypes. A pCR was achieved in 33.3, 50, and 52.9% of high TIL patients in luminal, HER2-enriched, and TNBC subtypes, respectively (p < 0.05). High TILs were linked to longer DFS and OS in TNBC and HER2-enriched breast cancers. In this first study of its kind from a low- and middle-income country, high TILs concentration was found to be a predictor of response to PST across all breast cancer subtypes. TILs concentration was found predictive of better DFS and OS in TNBC and HER2-enriched cancers. Prognostic role of TILs in luminal cancers was not so apparent.

Characterization and optimization of co-delivery Farnesol-Gingerol Niosomal formulation to enhance anticancer activities against breast cancer cells

The current investigation is designed to formulate and characterize an optimized Farnesol-Gingerol-loaded (N-Far/Gin) niosomal drug delivery system as a therapeutic approach for breast cancer. The formulation was optimized by altering the surfactant:cholesterol ratio, Span 60:Tween 60 ratio and lipid content, resulting in niosomes with acceptable encapsulation and a controlled release profile. The optimized niosomal formulation demonstrated excellent stability for up to two months with only slight alterations in size and drug encapsulation quality during the storage period. Furthermore, the results demonstrated a pH-dependent release pattern, with delayed drug release under physiological conditions (pH 7.4) and substantial drug release under acidic conditions (pH 5.4), meaning these niosomes display a potent therapeutic potential for breast cancer. Cytotoxicity assays showed a biocompatibility of N-Far/Gin with normal cells while exhibiting inhibitory activity on MCF7 and SKBR3 breast cancer cell lines. The N-Far/Gin down-regulated gene expression levels of BCL2, HER2, CDK4, CCND1, and CCNE while up-regulating gene expression levels of P21, BAX, CASP3, and CASP9 in breast cancer cell lines. Apoptosis assays indicated that N-Far/Gin induces apoptosis in both MCF7 and SKBR3 cell lines, which can be attributed to the synergic efficacy of the two agents. The ROS assay revealed high antioxidant activity of the N-Far/Gin formulation. The experimental findings from this study highlight the importance of highly biocompatible niosomal formulations to the future of nanomedicine; the co-delivery of two phytochemical compounds into cancer cells could enhance therapy effectiveness due to the synergistic impact.

Synergistic Anti-Angiogenic Effect of Combined VEGFR Kinase Inhibitors, Lenvatinib, and Regorafenib: A Therapeutic Potential for Breast Cancer.

Background: Breast cancer currently affects more than two million women worldwide, and its incidence is steadily increasing. One of the most essential factors of invasion and metastasis of breast cancer cells is angiogenesis and non-angiogenic vascularization. Lenvatinib and Regorafenib share the same anti-angiogenic effect by inhibiting vascular endothelial growth factor receptors (VEGFRs subtypes 1 to 3) and have been approved for treating different types of cancer. Methods: We investigated Lenvatinib and Regorafenib effects on a well-established in-vitro model of breast cancer using MCF-7 (estrogen, progesterone receptor-positive, and HER2-negative), MDA-MB-231 (triple negative), as well as Human Umbilical Vascular Endothelial Cell line (HUVEC) cell lines. We performed the cell viability assay on four groups of cells, which included a control group, a Lenvatinib treated only group, a Regorafenib treated only group, and a group treated with a combination of both drugs at 24, 48, and 72 h. Data were analyzed as means ± standard deviation, and the drug–drug interactions with Compusyn software. Cellular migration assay, tube formation assay, and Western blots were conducted to determine the functional and the protein expression of downstream signals such as Caspase-9, anti-apoptotic Survivin, P-ERK, and total-ERK in the control and treatment groups. Results: MCF-7 cells showed a reduction in cell survival rates with higher dosing and longer incubation periods with each drug and with the combination of drugs. A synergistic interaction was identified (CI < 1) with both drugs on MCF7 at different dose combinations and at a higher dose in MDA-MB-231 cells. Furthermore, there was a marked decrease in the anti-angiogenic effect of both drugs in tube formation assay using MDA-MB-231 cells and survivin protein expression in MCF-7, and those antitumor markers showed a better outcome in drug combination than the use of each drug alone. Conclusion: Our result is the first to report the synergistic anti-angiogenic potential of combination therapy of Lenvatinib and Regorafenib. Therefore, it shows their therapeutic potential in breast cancer, including the aggressive types. Further studies are warranted to confirm and explore this therapeutic approach.

A High Epigenetic Risk Score Shapes the Non-Inflamed Tumor Microenvironment in Breast Cancer.

Background: Epigenetic dysregulation via aberrant DNA methylation has gradually become recognized as an efficacious signature for predicting tumor prognosis and response to therapeutic targets. However, reliable DNA methylation biomarkers describing tumorigenesis remain to be comprehensively explored regarding their prognostic and therapeutic potential in breast cancer (BC). Methods: Whole-genome methylation datasets integrated from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were profiled (n = 1,268). A three-stage selection procedure (discovery, training, and external validation) was utilized to screen out the prominent biomarkers and establish a robust risk score from more than 300,000 CpG sites after quality control, rigorous filtering, and reducing dimension. Moreover, gene set enrichment analyses guided us to systematically correlate this epigenetic risk score with immunological characteristics, including immunomodulators, anti-cancer immunity cycle, immune checkpoints, tumor-infiltrating immune cells and a series of signatures upon modulating components within BC tumor microenvironment (TME). Multi-omics data analyses were performed to decipher specific genomic alterations in low- and high-risk patients. Additionally, we also analyzed the role of risk score in predicting response to several treatment options. Results: A 10-CpG-based prognostic signature which could significantly and independently categorize BC patients into distinct prognoses was established and sufficiently validated. And we hypothesize that this signature designs a non-inflamed TME in BC based on the evidence that the derived risk score is negatively correlated with tumor-associated infiltrating immune cells, anti-cancer immunity cycle, immune checkpoints, immune cytolytic activity, T cell inflamed score, immunophenoscore, and the vast majority of immunomodulators. The identified high-risk patients were characterized by upregulation of immune inhibited oncogenic pathways, higher TP53 mutation and copy number burden, but lower response to cancer immunotherapy and chemotherapy. Conclusion: Our work highlights the complementary roles of 10-CpG-based signature in estimating overall survival in BC patients, shedding new light on investigating failed events concerning immunotherapy at present.

The anticancer effect of the TLR4 inhibition using TAK‐242 (resatorvid) either as a single agent or in combination with chemotherapy: A novel therapeutic potential for breast cancer

Increasing pieces of evidence indicate that inflammatory processes facilitate tumorigenesis; tumor cells simulate the mechanisms by which innate immune cells produce pro-inflammatory cytokines to exploit them for their own survival and proliferation. Toll-like receptor 4 (TLR4), which serves as one of the most well-known receptors on the surface of the immune cells, is often expressed ectopically in the tumor cells resulting in tumor progression, invasion, and chemoresistance. In this study, we examined the anticancer effects of TAK-242, a small molecule inhibitor of TLR4, on different breast cancer cell lines: MCF7, SKBR3, MDA-MB-231, and BT-474. Our results showed that the TLR4 inhibition, as revealed by the downregulation of TLR4 downstream genes, exerted desirable cytotoxicity on the TLR4-expressing cells, at least partly, through the downregulation of EGFR and c-Myc genes. TAK-242 also inhibited the proliferation of anoikis-resistant cells and suppressed the clonal growth of the indicated cells. The results of this study propose a mechanistic pathway by which the inhibition of TLR4 using TAK-242 could augment apoptotic cell death through the alteration of both nuclear factor-кB- and p53-related apoptosis genes in breast cancer cells, especially cells with overexpression of TLR4. Taken together, this study supports the idea that the activation of inflammatory pathways may have a crucial role in breast cancer progression and the inhibition of TLR4 using TAK-242, either as a single agent or in combination, seems to be a novel promising strategy that could be clinically available in foreseeable future.

Development of a Novel Humanized Monoclonal Antibody to Secreted Frizzled-Related Protein-2 That Inhibits Triple-Negative Breast Cancer and Angiosarcoma Growth In Vivo.

We previously reported that secreted frizzled-related protein-2 (SFRP2) is expressed in a variety of tumors, including sarcoma and breast carcinoma, and stimulates angiogenesis and inhibits tumor apoptosis. Therefore, we hypothesized that a humanized SFRP2 monoclonal antibody (hSFRP2 mAb) would inhibit tumor growth. The lead hSFRP2 antibody was tested against a cohort of 22 healthy donors using a time course T-cell assay to determine the relative risk of immunogenicity. To determine hSFRP2 mAb efficacy, nude mice were subcutaneously injected with SVR angiosarcoma cells and treated with hSFRP2 mAb 4mg/kg intravenously every 3days for 3weeks. We then injected Hs578T triple-negative breast cells into the mammary fat pad of nude mice and treated for 40days. Control mice received an immunoglobulin (Ig) G1 control. The SVR and Hs578T tumors were then stained using a TUNEL assay to detect apoptosis. Immunogenicity testing of hSFRP2 mAb did not induce proliferative responses using a simulation index (SI) ≥ 2.0 (p < 0.05) threshold in any of the healthy donors. SVR angiosarcoma tumor growth was inhibited in vivo, evidenced by significant tumor volume reduction in the hSFRP2 mAb-treated group, compared with controls (n = 10, p < 0.001). Likewise, Hs578T triple-negative breast tumors were smaller in the hSFRP2 mAb-treated group compared with controls (n = 10, p < 0.001). The hSFRP2 mAb treatment correlated with an increase in tumor cell apoptosis (n = 11, p < 0.05). Importantly, hSFRP2 mAb treatment was not associated with any weight loss or lethargy. We present a novel hSFRP2 mAb with therapeutic potential in breast cancer and sarcoma that has no effect on immunogenicity.

Increased expression of ZNF 703 in breast cancer tissue: An opportunity for RNAi–NSAID combinatorial therapy

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to exhibit antitumor activities. Among the very well-known oncogenes in breast cancer is zinc finger protein 703 (ZNF703) and cyclooxygenase-2 (COX-2). Numerous reports indicate a direct link among apoptosis resistance, chemotherapy resistance, and increased expression of ZNF703. In the present study, the expression level of ZNF703 was compared in human breast cancer tissue, healthy breast tissue, and MCF-7 breast cancer cell line by a real-time PCR. We also investigated the inhibitory effect of anti-ZNF703 RNAi interference (RNAi) and ibuprofen, either individually or in combination, on MCF-7 cell survival and apoptosis. Results showed a 93.3% and fourfold increase in the expression of ZNF703 in breast cancer tissue and MCF-7 cell line, respectively. Ibuprofen inhibited the viability of MCF-7 cells in a concentration-dependent manner. Ibuprofen alone or in combination with anti-ZNF703 RNA reduced the expression of ZNF703, induced apoptosis, reduced mitochondrial membrane potential, and elevated BAX and LC3A in MCF-7 cells. Our results show that the combination of ibuprofen and anti-ZNF703 siRNA is more effective in promoting apoptosis than each treatment alone. We report that the combination of anti-ZNF703 RNAi with ibuprofen as the inhibitor of COX-2 is highly effective in inhibiting MCF-7 as a breast cancer cell line and shows therapeutic potential for breast cancer.

Pyridoxine 5'-phosphate oxidase is correlated with human breast invasive ductal carcinoma development.

Pyridoxine 5′-phosphate oxidase (PNPO) is a converting enzyme for an active form of vitamin B6. This study aims to evaluate the biological function and the regulatory mechanism of PNPO in human breast invasive ductal carcinoma (IDC). We unveiled for the first time that PNPO was upregulated in patients with IDC and was correlated with the overall survival of patients with metastasis at the later stages. Suppression of PNPO inhibited breast cancer cell proliferation, migration, invasion and colony formation, arrested cell cycle at the G2/M phase and induced cell apoptosis. PNPO was positively correlated with lncRNA MALAT1 which was negatively correlated with miR-216b-5p. PNPO was down-regulated and up-regulated by miR-216b-5p mimics and inhibitors, respectively, in breast cancer cells. A microRNA response element was found in both PNPO and MALAT1 transcripts for miR-216b-5p and the dual-luciferase reporter assay confirmed the binding of these transcripts. Knockdown of MALAT1 resulted in an increase of miR-216b-5p and a decrease of PNPO mRNA, indicating a regulatory mechanism of competing endogenous RNAs. Taken together, these results reveal the biological function and a regulatory mechanism of PNPO, in which the MALAT1/miR-216b-5p/PNPO axis may be important in IDC development. Targeting this axis may have therapeutic potential for breast cancer.

Serum Levels of Activins, Follistatins, and Growth Factors in Neoplasms of the Breast: A Case-Control Study.

Breast cancer is the most common malignancy in women. Noninvasive biomarkers are needed for its early diagnosis and/or prognosis. The aim of this case-control study was the comparison of serum activins, follistatins, and members of the IGF family levels in women with benign vs malignant breast neoplasms vs apparently healthy controls. Women with breast benign (n = 100) or malignant tumors (n = 145) and disease-free controls (n = 100) were recruited. Women with breast cancer were subsequently subdivided into recently diagnosed/treatment-naive (n = 112) and chemotherapy-treated (n = 33). Anthropometric, demographic, biochemical, and histological data were recorded. A breast cancer clinic in Thessaloniki, Greece. Serum levels of activin A, activin B, follistatin, follistatin-like (FSTL)-3, total IGF-1, total and intact insulin-like growth factor binding protein (IGFBP)-4 and pregnancy-associated plasma protein-A (PAPP-A) were measured with highly specific ELISA kits. In adjusted comparisons, substantial differences in FSTL-3, total and intact IGFBP-4, PAPP-A, and total IGF-1 were observed between groups. In logistic regression analysis, primarily total IGFBP-4 levels were independently associated with the overall presence of breast malignancy. FSTL-3 was the only variable that could distinguish between a benign vs malignant breast mass. In linear regression analysis, FSTL-3 was independently associated with tumor size. We showed that members of the IGF-1/IGFBP-4/PAPP-A axis and FSTL-3 may serve as surrogate markers in breast cancer. Future mechanistic and longitudinal studies and/or clinical trials are needed to explore the efficacy of these molecules as noninvasive biomarkers and their possible therapeutic potential in breast cancer.

New Bis copper complex ((Z) -4 - ((4-chlorophenyl) amino) -4-oxobut-2-enoyl) oxy): Cytotoxicity in 4T1 cells and their toxicogenic potential in Swiss mice

Copper (II) complexes are promising in the development of new synthetic models for cancer treatment. In this context, we synthesized a new copper complex containing the pharmacophore group 1,4-dioxo-2-butenyl, the Bis(((Z)-4-((4-chlorophenyl) amino)-4-oxobut-2-enoyl)oxy) copper compound and we evaluated its antitumor activity in 4 T1 murine mammary adenocarcinoma cells and their toxicogenic effect in Swiss mice. The compound demonstrated cytotoxicity and genotoxicity to 4 T1 cells, and after cell cycle arrest in G1, which occurred by the increase in ATM and p21 expression, it induced the cells to apoptosis by increasing BAX and caspase-7. In vivo the compound was genotoxic in mice but did not show permanent damage, observed by the absence of increased micronucleus frequency, and did not induce changes in the biometric parameters of the animals. These results indicate that the new copper complex, described firstly in this work, presents therapeutic potential for breast cancer.

Design, synthesis and structure-activity relationship of a focused library of β-phenylalanine derivatives as novel eEF2K inhibitors with apoptosis-inducing mechanisms in breast cancer

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/calmudulin-dependent protein kinase, belonging to a small family of an atypical Ser/Thr-protein kinase. eEF2K has been recently reported to be highly activated or overexpressed in many types of cancer; therefore, eEF2K would be regarded as a promising therapeutic target. In this study, we discovered a β-phenylalanine scaffold by virtual high-throughput screening, as well as designed and synthesized 46 derivatives with assessment of inhibition activity against eEF2K and cytotoxicity. After several rounds of kinase and anti-proliferative activity screening, we discovered an eEF2K inhibitor (21l) with best eEF2K enzymatic activity (IC50 of 5.5 μM) and anti-proliferative activity (MDA-MB-231 cells, IC50 of 12.6 μM, MDA-MB-436 cells, IC50 of 19.8 μM). Moreover, we found that 21l could induce cell death via the apoptotic pathways in MDA-MB-231 and MDA-MB-436 cells. Subsequently, we evaluated its anti-tumor activity and apoptosis-inducing mechanisms in vivo. These results suggested that 21l inhibited tumor growth by apoptosis in the xenograft mouse model of breast cancer (MDA-MB-231 and MDA-MB-436). Collectively, our results demonstrate a novel small-molecule inhibitor targeting eEF2K with mechanism of apoptosis and a therapeutic potential in breast cancer.

Investigating the therapeutic potential and mechanism of curcumin in breast cancer based on RNA sequencing and bioinformatics analysis.

Breast cancer is a prevalent cancer in female. This study aims to investigate the therapeutic potential and mechanism of curcumin in breast cancer. After cultivation, human breast cancer cells (MCF-7 cells) were treated with 0.1% (v/v) 15µmol/ml curcumin-dimethylsulfoxide solution and 0.1% (v/v) dimethylsulfoxide, respectively, at 37°C and 5% CO2 for 48h. Total RNA was extracted, cDNA library was constructed, and cDNAs were amplified and sequenced. After data preprocessing, the Cufflinks software was utilized to identify differentially expressed genes (DEGs, |log2 fold change|>0.5 and p value<0.05). Then, functional and pathway enrichment analyses were performed through DAVID (p value<0.05) and WebGestalt [false discovery rate (FDR)<0.05], respectively. Furthermore, drug and disease association analyses (FDR<0.05) were conducted through WebGestalt and DAVID, respectively. STRING was employed to construct protein-protein interaction (PPI) network (combined score>0.4). After DEGs screening, 347 DEGs were identified. Up-regulated DEGs were enriched in 14 functions and 3 pathways, and associated with 12 drugs. Down-regulated DEGs were enriched in 14 functions and 9 pathways, and associated with 14 drugs. Moreover, 5 DEGs were associated with breast cancer, including PGAP3, MAP3K1, SERPINE1, PON2, and GSTO2. PPI network was constructed, and the top DEGs were FOS, VIM, FGF2, MAPK1, SPARC, TOMM7, PSMB10, TCEB2, SOCS1, COL4A1, UQCR11, SERPINE1, and ISG15. Curcumin might have therapeutic potential in breast cancer through regulating breast cancer-related genes, including SERPINE1, PGAP3, MAP3K1, MAPK1, GSTO2, VIM, SPARC, and FGF2. However, validations are required.