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Cancer stands as one of the most impactful illnesses in the modern world, primarily owing to its lethal consequences. The fundamental concern in this context likely stems from delayed diagnoses in patients. Hence, detecting various forms of cancer is imperative. A formidable challenge in cancer research has been the diagnosis and treatment of this disease. Early cancer diagnosis is crucial, as it significantly influences subsequent therapeutic steps. Despite substantial scientific efforts, accurately and swiftly diagnosing cancer remains a formidable challenge. It is well known that the field of cancer diagnosis has effectively included electrochemical approaches. Combining the remarkable selectivity of biosensing components—such as aptamers, antibodies, or nucleic acids—with electrochemical sensor systems has shown positive outcomes. In this study, we adapt a novel electrochemical biosensor for cancer detection. This biosensor, based on a glassy carbon electrode, incorporates a nanocomposite of reduced graphene oxide/Fe 3 O 4 /Nafion/polyaniline. We elucidated the modification process using SEM, TEM, FTIR, RAMAN, VSM, and electrochemical methods. To optimize the experimental conditions and monitor the immobilization processes, electrochemical techniques such as CV, EIS, and SWV were employed. The calibration graph has a linear range of 10 2 –10 6  cells mL −1 , with a detection limit of 5 cells mL −1 .

The natural compound sinularin, isolated from marine soft corals, is antiproliferative against several cancers, but its possible selective killing effect has rarely been investigated. This study investigates the selective killing potential and mechanisms of sinularin-treated breast cancer cells. In 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H- tetrazolium, inner salt (MTS) assay, sinularin dose-responsively decreased the cell viability of two breast cancer (SKBR3 and MDA-MB-231) cells, but showed less effect on breast normal (M10) cells after a 24 h treatment. According to 7-aminoactinomycin D (7AAD) flow cytometry, sinularin dose-responsively induced the G2/M cycle arrest of SKBR3 cells. Sinularin dose-responsively induced apoptosis on SKBR3 cells in terms of a flow cytometry-based annexin V/7AAD assay and pancaspase activity, as well as Western blotting for cleaved forms of poly(ADP-ribose) polymerase (PARP), caspases 3, 8, and 9. These caspases and PARP activations were suppressed by N-acetylcysteine (NAC) pretreatment. Moreover, sinularin dose-responsively induced oxidative stress and DNA damage according to flow cytometry analyses of reactive oxygen species (ROS), mitochondrial membrane potential (MitoMP), mitochondrial superoxide, and 8-oxo-2′-deoxyguanosine (8-oxodG)). In conclusion, sinularin induces selective killing, G2/M arrest, apoptosis, and oxidative DNA damage of breast cancer cells.

Three-dimensional spheroids of non-malignant MCF10A and malignant SKBR3 breast cells were used for subsequent 3D Cell-SELEX to generate aptamers for specific binding and treatment of breast cancer cells. Using 3D Cell-SELEX combined with Next-Generation Sequencing and bioinformatics, ten abundant aptamer families with specific structures were identified that selectively bind to SKBR3, and not to MCF10A cells. Multivalent aptamer polymers were synthesized by co-polymerization and analyzed for binding performance as well as therapeutic efficacy. Binding performance was determined by confocal fluorescence imaging and revealed specific binding and efficient internalization of aptamer polymers into SKBR3 spheroids. For therapeutic purposes, DNA sequences that intercalate the cytotoxic drug doxorubicin were co-polymerized into the aptamer polymers. Viability tests show that the drug-loaded polymers are specific and effective in killing SKBR3 breast cancer cells. Thus, the 3D-selected aptamers enhanced the specificity of doxorubicin against malignant over non-malignant breast cells. The innovative modular DNA aptamer platform based on 3D Cell SELEX and polymer multivalency holds great promise for diagnostics and treatment of breast cancer.

Breast cancer is one of the most diffuse cancers in the world and despite the availability of the different drugs employed against it, the need for new and particularly more specific molecules is ever growing. In this framework, natural products are increasingly assuming an important role as new anticancer drugs. Aloe-emodin (AE) is one of the best characterized molecules in this field. The functionalization of bioactive natural products with selected peptide sequences to enhance their bioavailability and specificity of action is a powerful and promising strategy. In this study, we analyzed the cell specificity, cell viability effects, intracellular distribution, and immune cell response of a new peptide conjugate of Aloe-emodin in SKBR3 and A549 cell lines by means of viability tests, flow cytometry, and confocal microscopy. The conjugate proved to be more effective at reducing cell viability than AE in both cell lines. Furthermore, the results showed that it was mainly internalized within the SKBR3 cells, showing a nuclear localization, while A459 cells displayed mainly a cytoplasmic distribution. A preserving effect of the conjugate on NKs’ cell function was also observed. The designed conjugate showed a promising specific activity towards HER2-expressing cells coupled with an enhanced water solubility and a higher cytotoxicity; thus, the resulting proof-of-concept molecule can be further improved as an anticancer compound.

Background/Aim: Copine 1 (CPNE1) is a calciumdependent phospholipid protein that has been shown to regulate the AKT serine/threonine kinase 1 (AKT) signaling pathway to mediate its function in various cell types. However, little is known about the physiological function of this protein in breast cancer cells. We aimed to investigate the prognostic and therapeutic value of CPNE1 in erb-b2 receptor tyrosine kinase 2 [human epidermal growth factor receptor 2 (HER2)]-positive and luminal A subtypes of breast cancer. Materials and Methods: Western blotting, cell viability, wound-healing and invasion assays were performed on SK-BR3 and MCF-7 breast cancer cells with forced overexpression of CPNE1. CPNE1 immunohistochemical (IHC) staining and bioinformatics analysis were performed on specimens from patients with breast cancer and compared to normal breast samples. Results: CPNE1 overexpression promoted AKT activation, and increased cell viability and cell motility in SK-BR3 and MCF-7 breast cancer cells. In addition, invasive capabilities of SK-BR3 cells were increased by the overexpression of CPNE1. The expression levels of CPNE1 were higher in HER2-positive and luminal A subtypes of human breast cancer tissues compared with those in adjacent normal tissues. Furthermore, CPNE1 expression was increased in RNA microarray analysis of samples from patients with breast cancer compared to normal breast samples. Conclusion: CPNE1 may play a key role in the pathophysiology of HER2-positive and luminal A subtypes of breast cancer.

Astaxanthin (AST) is related to apoptosis but the details of the mechanism of how AST makes apoptosis is not clear. The present study investigated apoptotic effects of AST to SKBR3, a breast cancer cell line in detail. Cell viability assay showed cellular proliferation and morphological changes of the cells were observed under AST treatment. FACS analysis indicated that AST blocked cell cycle progression at G0/G1, suppressed proliferation dose-dependently, and induced apoptosis of the cells. The apoptosis of the cells by AST was further demonstrated through the decreased expression level of mutp53 and cleaved a PARP-1 fragment, respectively. In addition, AST induced the intrinsic apoptosis of the cells by activation of Bax/Bcl2, cleaved caspase-3, and cleaved caspase-9 as well as the phosphorylation of ERK1/2, JNK, and p38. Furthermore, AST decreased production of intracellular reactive oxygen species as well as modulated expressions of superoxide dismutases and Pontin, an anti-apoptotic factor. Co-immunoprecipitation assay revealed AST reduced interaction between Pontin and mutant p53. Taken together, these studies proved that AST regulates the expression of apoptotic molecules to induce intrinsic apoptosis of the cells, suggesting AST therapy might provide an alternative for improving the efficacies of other anti-cancer therapies for breast cancer.

Background: With widespread therapeutic advancement, targeted anticancer therapeutics are taking over traditional treatment protocols. Nevertheless, the resistance to targeted therapeutics has halted the enthusiastic treatment response. An example of targeted therapy is Lapatinib. Lapatinib is a tyrosine kinase inhibitor used in HER2-positive breast cancer. It is widely used in HER2-positive metastatic breast cancer in combination with other drugs. Methods: This study's main objective was to provide a plausible mechanistic insight into lapatinib's resistance in two HER2 positive breast cancer cell lines, SKBR3 and BT-474. We performed gene set analysis to identify the differentially expressed genes (DEG) in response to treatment with lapatinib from the gene expression profiles obtained from GSE38376 and GSE16179. The DEG was then analyzed by Ingenuity Pathway Analysis (IPA). Results: The IPA analysis showed that the increased expression of Hypoxia-inducible factor-1 alpha (HIF-1α) and Wnt/β-catenin and their related networks were associated with resistance and poor prognosis in SKBR3 and BT-474 cell lines, respectively. Although both cell lines are categorized as HER2 positive cell lines and in some reports were used interchangeably, in our hands, the two cell lines exhibited different biological pathways underlying resistance to lapatinib. In addition, among the other top canonical pathways, TNF was identified as the top upstream regulator in SKBR3 cell lines, whereas the Microphthalmia-associated transcription factor (MITF) was predicted as a top regulator in BT-474 cell lines. Conclusions: This study highlights the relevance of HIF-1α and Wnt/β-catenin compensatory networks in resistance toward lapatinib. Our findings outline the activation of angiogenesis and invasion processes in resistant cells with differential underlining gene networks in two different HER2 positive cell lines. The two cell lines reflect two different types of breast cancer, and hence the treatment strategy to avoid resistance should be planned differently.

Modern cancer treatment strategies aim at achieving cancer remission by using targeted and personalized therapies, as well as harnessing the power of the immune system to recognize and eradicate the cancer cells. To overcome a relatively short-lived response due to resistance to the administered drugs, combination therapies have been pursued. The objective of this study was to use high-throughput data generation technologies such as mass spectrometry and proteomics to investigate the broader implications, and to expand the outlook, of such therapeutic approaches. Specifically, we investigated the systems-level response of a breast cancer cell line model to a mixture of kinase inhibitors that has not been adopted yet as a standard therapeutic regime. Two critical pathways that sustain the growth and survival of cancer cells, EGFR and PI3K/AKT, were inhibited in SKBR3/HER2+ breast cancer cells with Lapatinib (Tyr kinase inhibitor) and Ipatasertib (Ser/Thr kinase inhibitor), and the landscape of the affected biological processes was investigated with proteomic technologies. Over 800 proteins matched by three unique peptide sequences were affected by exposing the cells to the drugs. The work corroborated the anti-proliferative activity of Lapatinib and Ipatasertib and uncovered a range of impacted cancer-supportive hallmark processes, among which immune response, adhesion, and migration emerged as particularly relevant to the ability of drugs to effectively suppress the proliferation and dissemination of cancer cells. Changes in the expression of key cancer drivers such as oncogenes, tumor suppressors, EMT and angiogenesis regulators underscored the inhibitory effectiveness of drugs on cancer proliferation. The supplementation of Lapatinib with Ipatasertib further affected additional transcription factors and proteins involved in gene expression, trafficking, DNA repair, and development of multidrug resistance. Furthermore, over fifty of the impacted proteins represent approved or investigational targets in the DrugBank database, which through their protein-protein interaction networks can inform the selection of effective therapeutic partners. Altogether, the exposure of SKBR3/HER2+ cells to Lapatinib and Ipatasertib kinase inhibitors uncovered a broad plethora of yet untapped opportunities that can be further explored for enhancing the anti-cancer effects of each drug as well as of many other multi-drug therapies that target the EGFR/ERBB2 and PI3K/AKT pathways.

The anticancer drug ibrutinib (IB), also known as PCI-32765, is a compound that irreversibly inhibits Bruton’s tyrosine kinase (BTK) and was initially developed as a treatment option for B-cell lineage neoplasms. Its action is not limited to B-cells, as it is expressed in all hematopoietic lineages and plays a crucial role in the tumor microenvironment. However, clinical trials with the drug have resulted in conflicting outcomes against solid tumors. In this study, folic acid-conjugated silk nanoparticles were used for the targeted delivery of IB to the cancer cell lines HeLa, BT-474, and SKBR3 by exploiting the overexpression of folate receptors on their surfaces. The results were compared with those of control healthy cells (EA.hy926). Cellular uptake studies confirmed total internalization of the nanoparticles functionalized by this procedure in the cancer cells after 24 h, compared to nanoparticles not functionalized with folic acid, suggesting that cellular uptake was mediated by folate receptors overexpressed in the cancer cells. The results indicate that the developed nanocarrier can be used for drug targeting applications by enhancing IB uptake in cancer cells with folate receptor overexpression.

PurposeDysregulation of HER2 signaling pathway in breast cancer is well documented. Our bioinformatics analysis predicted hsa-miR-512-3p (miR-512-3p) as a bona fide regulator of HER2 as well as HER3, PIK3R2, and AKT1 genes. Then, we intended to examine the effect of miR-512-3p on the predicted target genes that are involved in HER2 signaling pathway.Methods and resultsRT-qPCR results indicated lower expression of miR-512-3p in breast cancer specimens, compared to their normal pairs. Overexpression of miR-512-3p resulted in HER2, HER3, PIK3R2, and AKT1 gene downregulation, detected by RT-qPCR and the result was confirmed by western analysis and ELIZA test against p-AKT, BAX, FADD, and HER2 proteins in SKBR3 cells, respectively. Then, dual-luciferase assay supported the direct interaction of miR-512-3p with 3′UTR sequences of HER2, HER3, PIK3R2, and AKT1 target genes. When miR-512-3p was overexpressed, BAX/BCL2 expression ratio and proportion of sub-G1 cell population were increased in transfected SKBR3 cells, detected by RT-qPCR and flow cytometry, respectively. These results were consistent with the decreased viability of transfected cells, documented by MTT assay. In addition, results were consistent with the upregulation of BAX, BAK, BOK, PTEN, P53, and P21 genes and downregulation of CCND1 gene in SKBR3 cells. Although the overexpression of miR-512 resulted in cell cycle arrest at Sub-G1 stage in MDA-MB-231 cells, this effect seemed independent of targeting HER2, HER3, PIK3R2, and AKT1 target genes.ConclusionOverall, results indicated that miR-512-3p acts as a cell-type-specific tumor suppressor, through targeting HER2, HER3, PIK3R2, and AKT1 transcripts. These results suggest miR-512-3p as a potential candidate marker for breast cancer diagnosis.