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Breast cancer (BC) caused 685,000 deaths globally in 2020, earning the title of the most common type of tumor among females. With a multifactorial genesis, BC is influenced by several factors such as age, genetic and epigenetic predisposition, and an individual's exposome, and its classification is based on morphological/histological, invasiveness, and molecular futures. Extracellular vesicles (EVs) are cell-derived lipid-bilayer-delimited nanoparticles, which are distinguishable by size, genesis, and the markers expressed in exosomes (40 to 150 nm), microvesicles (40 to 10,000 nm), and apoptotic bodies (100–5000 nm). Produced in physiological and pathological cellular contexts, EVs are shuttles of biological material and are implicated in cell-to-cell communications, thus attracting significant interest in diagnostic and drug delivery research. We report and discuss the latest evidence regarding the important role of EVs in BC, deepening their implication in tumorigenesis and metastatic mechanisms. On the other hand, the use of BC-derived EVs as prognostic biomarkers and therapeutic approaches is undergoing investigation. Hence, EVs have become new weapons in precision medicine; however, only with the support of advanced algorithms such as artificial intelligence (AI) can we develop a wide range of information. Looking ahead, it is possible to see the application of AI in the prognosis and diagnosis of different pathologies. [ABSTRACT FROM AUTHOR]

The hydrogels prepared with alginate and chitosan polymers were prepared to deliver the shRNA-encoding plasmid (pshRNA) to MDA-MB-231 cells for the inhibition of β-catenin (CTNNB1), which was reported to be overexpressed in breast cancer. Polyion complex hydrogels prepared using sodium alginate and chitosan were characterized by Fourier transform infrared spectrometry (FTIR) analysis, scanning electron microscope (SEM) analysis, swelling, and degradation properties. After the release properties and serum stability of pshRNA-loaded hydrogels were determined, their cytotoxicity, transfection efficacy, and effects on CTNNB1 expression were investigated in MDA-MB-231 cells. All hydrogels were shown to protect pshRNA from the enzymatic activity of serum and to deliver pshRNA to cells efficiently. As a result of transfection studies, pshRNA-loaded hydrogels reduced CTNNB1 expression by up to 30.25%. Cell viability also decreased by 38% in cells treated with 2.5% (w/v) alginate-chitosan hydrogel containing pshRNA targeting CTNNB1. Alginate-chitosan hydrogels were shown to be a suitable matrix system for local gene delivery. [ABSTRACT FROM AUTHOR]

In order to identify new targets and treatment modalities for breast cancer, we searched the literature for circular RNAs (circRNAs) with efficacy in preclinical breast cancer-related in vivo models. From our search, we identified 26 up-regulated and six down-regulated circRNAs which mediate efficacy in breast cancer-related preclinical in vivo models. We discuss reconstitution and inhibition of the identified circRNAs, as well as druggability and validation of the targets identified in the context of chemoresistance, inhibition of proliferation and metastasis. Pathways driven by suppressors of cytokines and high-mobility group proteins, nuclear factor ĸB and Hippo signaling emerged as important drivers of tumor growth and metastasis. The role of trefoil factor-1 with respect to metastasis of estrogen receptorpositive breast cancer also merits further investigation. In addition, mucin 19 has emerged as an unexplored target for treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Mitochondrial oxidative phosphorylation (OXPHOS) system dysfunction in cancer cells has been exploited as a target for anti-cancer therapeutic intervention. The downregulation of CR6-interacting factor 1 (CRIF1), an essential mito-ribosomal factor, can impair mitochondrial function in various cell types. In this study, we investigated whether CRIF1 deficiency induced by siRNA and siRNA nanoparticles could suppress MCF-7 breast cancer growth and tumor development, respectively. Our results showed that CRIF1 silencing decreased the assembly of mitochondrial OXPHOS complexes I and II, which induced mitochondrial dysfunction, mitochondrial reactive oxygen species (ROS) production, mitochondrial membrane potential depolarization, and excessive mitochondrial fission. CRIF1 inhibition reduced p53-induced glycolysis and apoptosis regulator (TIGAR) expression, as well as NADPH synthesis, leading to additional increases in ROS production. The downregulation of CRIF1 suppressed cell proliferation and inhibited cell migration through the induction of G0/G1 phase cell cycle arrest in MCF-7 breast cancer cells. Similarly, the intratumoral injection of CRIF1 siRNA-encapsulated PLGA nanoparticles inhibited tumor growth, downregulated the assembly of mitochondrial OXPHOS complexes I and II, and induced the expression of cell cycle protein markers (p53, p21, and p16) in MCF-7 xenograft mice. Thus, the inhibition of mitochondrial OXPHOS protein synthesis through CRIF1 deletion destroyed mitochondrial function, leading to elevated ROS levels and inducing antitumor effects in MCF-7 cells. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the first worldwide most frequent cancer in both sexes and the most commonly diagnosed in females. Although BC mortality has been thoroughly declining over the past decades, there are still considerable differences between women diagnosed with early BC and when metastatic BC is diagnosed. BC treatment choice is widely dependent on precise histological and molecular characterization. However, recurrence or distant metastasis still occurs even with the most recent efficient therapies. Thus, a better understanding of the different factors underlying tumor escape is mainly mandatory. Among the leading candidates is the continuous interplay between tumor cells and their microenvironment, where extracellular vesicles play a significant role. Among extracellular vesicles, smaller ones, also called exosomes, can carry biomolecules, such as lipids, proteins, and nucleic acids, and generate signal transmission through an intercellular transfer of their content. This mechanism allows tumor cells to recruit and modify the adjacent and systemic microenvironment to support further invasion and dissemination. By reciprocity, stromal cells can also use exosomes to profoundly modify tumor cell behavior. This review intends to cover the most recent literature on the role of extracellular vesicle production in normal and cancerous breast tissues. Specific attention is paid to the use of extracellular vesicles for early BC diagnosis, follow-up, and prognosis because exosomes are actually under the spotlight of researchers as a high-potential source of liquid biopsies. Extracellular vesicles in BC treatment as new targets for therapy or efficient nanovectors to drive drug delivery are also summarized. [ABSTRACT FROM AUTHOR]

Citrus (genus Citrus L.) fruits are essential sources of bioactive compounds with antioxidant properties, such as flavonoids. These polyphenolic compounds are divided into subclasses, in which flavanones are the most prominent. Among them, naringenin and hesperidin are emerging compounds with anticancer potential, especially for breast cancer (BC). Several mechanisms have been proposed, including the modulation of epigenetics, estrogen signaling, induction of cell death via regulation of apoptotic signaling pathways, and inhibition of tumor invasion and metastasis. However, this information is sparse in the literature and needs to be brought together to provide an overview of how naringenin and hesperidin can serve as therapeutic tools for drug development and as a successful co-adjuvant strategy against BC. This review detailed such mechanisms in this context and highlighted how naringenin and hesperidin could interfere in BC carcinogenesis and be helpful as potential alternative therapeutic sources for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Based on the latest research progresses, application of immune checkpoint inhibitors (ICIs) has shown promise in treating breast cancer. Moreover, novel ICIs based combined therapy has been sought to further enhance the curative effect. This review brings up a whole new conception of combined strategy by adding miRNA therapy into immune checkpoint blockade (ICB), based on the fact that miRNAs targeting multiple immune checkpoint molecules are believed to enhance the efficacy of ICB by mimicking combination therapy. Potential miRNAs have been summarized in this study. We also discussed the potential side-effects and solutions of applying such method. To thoroughly evaluate the role of miRNAs with multiple immune checkpoint molecules to act as a novel additive therapy for ICB in cancer treatment in future study, may further improve the clinical benefit of cancer immunotherapy. Breast cancer is the most common cancer type and the leading cause of cancer-associated mortality in women worldwide. In recent years, immune checkpoint inhibitors (ICIs) have made significant progress in the treatment of breast cancer, yet there are still a considerable number of patients who are unable to gain lasting and ideal clinical benefits by immunotherapy alone, which leads to the development of a combination regimen as a novel research hotspot. Furthermore, one miRNA can target several checkpoint molecules, mimicking the therapeutic effect of a combined immune checkpoint blockade (ICB), which means that the miRNA therapy has been considered to increase the efficiency of ICIs. In this review, we summarized potential miRNA therapeutics candidates which can affect multiple targets of immune checkpoints in breast cancer with more therapeutic potential, and the obstacles to applying miRNA therapeutically through the analyses of the resources available from a drug target perspective. We also included the content of "too many targets for miRNA effect" (TMTME), combined with applying TargetScan database, to discuss adverse events. This review aims to ignite enthusiasm to explore the application of miRNAs with multiple targets of immune checkpoint molecules, in combination with ICIs for treating breast cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a dramatic illness that ranks among the most pressing health concerns facing humanity and necessitates a proactive approach to treatment. Phytochemicals are regarded as interesting molecules for the development of anticancer drugs due to their pleiotropic effects on broad targets. The actions of phytochemicals are focused on tumor cells alone, with no negative effects on normal cells. The intricate process of carcinogenesis involves numerous signaling cascades. This study examined the effects of four organ extracts from a Mediterranean endemic plant, Cladanthus mixtus, on human tumor cells. To the best of our knowledge, this is the first study on this plant from northern Morocco showing relevant antiproliferative activity against two cancer cell lines and one non-tumoral cell line. Many of the chemotherapeutic drugs for the treatment of cancer are molecules identified and isolated from plants or their synthetic derivatives. This work aimed to identify the bioactive compounds using LC-MS and GC-MS and to evaluate the anticancer activity of the methanolic extracts of roots, stems, leaves, and flowers from Cladanthus mixtus. The anticancer activity was evaluated in vitro against two cancer cell lines: human breast carcinoma (MCF-7) and human prostate carcinoma (PC-3), using the MTT assay and microscopic observation. A human normal lung fibroblast (MRC-5) was included to determine the extract's safety for non-tumoral cells. The chemical composition results by LC-MS analysis revealed the presence of 24 phenolic compounds. Furthermore, GC-MS analysis allowed the identification of many biomolecules belonging to terpenoids, esters, alcohols, alkanes, fatty acids, organic acids, benzenes, phenols, ketones, carbonyls, amines, sterols, and other groups. The findings suggest that the majority of C. mixtus extracts have antiproliferative activity against two cancer cell lines, MCF-7 and PC-3, and one non-tumoral cell line, MRC-5. The activity was dose-dependent, and the highest effect was obtained with leaf extract in the two cancer cell lines. Moreover, these extracts demonstrated an acceptable toxicological profile against normal cells. Overall, C. mixtus extracts revealed promising antitumor properties provided by their phytochemical composition. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is one of the most challenging cancers to treat, accounting for many cancer‐related deaths. Over some years, chemotherapy, hormone treatment, radiation, and surgeries have been used to treat cancer. Unfortunately, these treatment options are unsuccessful due to crucial adverse reactions and multidrug tolerance/resistance. Although it is clear that substances in the nutraceuticals category have a lot of anti‐cancer activity, using a supplementary therapy strategy, in this case, could be very beneficial. Nutraceuticals are therapeutic agents, which are nutrients that have drug‐like characteristics and can be used to treat diseases. Plant nutraceuticals categorized into polyphenols, terpenoids, vitamins, alkaloids, and flavonoids are part of health food products, that have great potential for combating BC. Nutraceuticals can reduce BC's severity, limit malignant cell growth, and modify cancer‐related mechanisms. Nutraceuticals acting by attenuating Hedgehog, Nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), Notch, and Wnt/β‐catenin signaling are the main pathways in controlling the self‐renewal of breast cancer stem cells (BCSCs). This article reviews some important nutraceuticals and their modes of action, which can be very powerful versus BC. Practical applications: Nutraceuticals' importance to the control and diagnosis of breast cancer is undeniable and cannot be overlooked. Natural dietary compounds have a wide range of uses and have been used in traditional medicine. In addition, these natural chemicals can enhance the effectiveness of other traditional medicines. They may also be used as a treatment process independently because of their capacity to affect several cancer pathways. This study highlights a variety of natural chemicals, and their mechanisms of action, routes, synergistic effects, and future potentials are all examined. [ABSTRACT FROM AUTHOR]

The increase in cancer cases is undoubtedly affecting the development of new therapeutic approaches. Polymeric nanoparticles are of great interest. Due to their relatively small size, the possibility of incorporating into them medicinal substances and the ease with which their physicochemical properties may be manipulated, they are being used as anticancer drug delivery systems. The aim of this review is to focus on the use of nanoscale polymeric particles in the treatment of colorectal cancer, breast cancer, ovarian cancer and glioblastoma multiforme, and to consider their potential use in cancer gene therapy. According to several reports, the use of polymer nanoparticles as drug carriers is promising in solid tumors. With their application, it is possible to precisely deliver medicinal substances to the tumor structure, to overcome the blood–brain barrier in the case of brain tumors, to reduce the side effects of anticancer agents on normal cells and to achieve a therapeutic effect with a lower drug dose. Additionally, a number of reports indicate that they can also be used in combination with other methods of cancer treatment, mainly radiotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The high rate of cancers in both humans and in animals along with their poor overall survival pose a major challenge in medicine. Therefore, a large amount of research has been focused on improving the diagnosis and efficacy of treatment. In the case of human breast cancer (HBC) there are several diagnostic and treatment protocols, which greatly decrease the rate of death among patients. In veterinary medicine, canine mammary tumors (CMTs), which are very similar to HBC, are still poorly studied, lacking in treatment options, they are diagnosed at an advanced stage, and usually have a bad prognosis. Therefore, early diagnosis of CMTs and introducing personalized treatment are necessary. This article is a summary of possible novel diagnostic techniques as well as the main biomarkers that seem to improve treating CMTs. Canine mammary tumors (CMTs) are considered a serious clinical problem in older bitches. Due to the high malignancy rate and poor prognosis, an early diagnosis is essential. This article is a summary of novel diagnostic techniques as well as the main biomarkers of CMTs. So far, CMTs are detected only when changes in mammary glands are clinically visible and surgical removal of the mass is the only recommended treatment. Proper diagnostics of CMT is especially important as they represent a very diverse group of tumors and therefore different treatment approaches may be required. Recently, new diagnostic options appeared, like a new cytological grading system of CMTs or B-mode ultrasound, the Doppler technique, contrast-enhanced ultrasound, and real-time elastography, which may be useful in pre-surgical evaluation. However, in order to detect malignancies before macroscopic changes are visible, evaluation of serum and tissue biomarkers should be considered. Among them, we distinguish markers of the cell cycle, proliferation, apoptosis, metastatic potential and prognosis, hormone receptors, inflammatory and more recent: metabolomic, gene expression, miRNA, and transcriptome sequencing markers. The use of a couple of the above-mentioned markers together seems to be the most useful for the early diagnosis of neoplastic diseases as well as to evaluate response to treatment, presence of tumor progression, or further prognosis. Molecular aspects of tumors seem to be crucial for proper understanding of tumorigenesis and the application of individual treatment options. [ABSTRACT FROM AUTHOR]

Breast cancer is a kind of malignant tumor disease that poses a serious threat to human health. Its biological characteristics of rapid proliferation and delayed angiogenesis, lead to intratumoral hypoxia as a common finding in breast cancer. HIF as a transcription factor, mediate a series of reactions in the hypoxic microenvironment, including metabolic reprogramming, tumor angiogenesis, tumor cell proliferation and metastasis and other important physiological and pathological processes, as well as gene instability under hypoxia. In addition, in the immune microenvironment of hypoxia, both innate and acquired immunity of tumor cells undergo subtle changes to support tumor and inhibit immune activity. Thus, the elucidation of tumor microenvironment hypoxia provides a promising target for the resistance and limited efficacy of current breast cancer therapies. We also summarize the hypoxic mechanisms of breast cancer treatment related drug resistance, as well as the current status and prospects of latest related drugs targeted HIF inhibitors. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy in women and is rated among one of the three common malignancies worldwide in combination with colon and lung cancer. The escalating mortality rate of breast cancer patients has captivated the attention of the present-day researchers to come up with new management options. According to WHO, early detection, timely diagnosis and comprehensive breast cancer management are the three cornerstones for controlling breast cancer incidences per year. Multidisciplinary theragnostic approaches for simultaneous diagnosis and treatment of breast cancer have further enriched the therapeutic arsenal. Imaging and biopsy play a significant role in the diagnosis of breast cancer. The treatment plan mostly initiates with general surgery or radiation therapy followed up with adjuvant and/or neoadjuvant therapy. Conventional chemotherapeutics in breast cancer suffer from toxicity and lack of site specificity. Bio-safe gold nanoparticles hold sufficient promise for bridging this gap. Diverse phytochemicals-based synthesis routes to arrive at nano-dimensional gold with spotlight on reaction mechanisms, reaction variables, specific advantages, toxicity and their influence in breast cancer conditions are the focus of this work. This review marks the first attempt to explore the potential of phytochemical-derived nano-gold in breast cancer treatment. [ABSTRACT FROM AUTHOR]

Cell surface thiols can be targeted by thiol-reactive groups of various materials such as peptides, nanoparticles, and polymers. Here, we used the maleimide group, which can rapidly and covalently conjugate with thiol groups, to prepare surface-modified liposomes (M-Lip) that prolong retention of doxorubicin (Dox) at tumor sites, enhancing its efficacy. Surface modification with the maleimide moiety had no effect on the drug loading efficiency or drug release properties. Compared to unmodified Lip/Dox, M-Lip/Dox was retained longer at the tumor site, it was taken up by 4T1 cells to a significantly greater extent, and exhibited stronger inhibitory effect against 4T1 cells. The in vivo imaging results showed that the retention time of M-Lip at the tumor was significantly longer than that of Lip. In addition, M-Lip/Dox also showed significantly higher anticancer efficacy and lower cardiotoxicity than Lip/Dox in mice bearing 4T1 tumor xenografts. Thus, the modification strategy with maleimide may be useful for achieving higher efficient liposome for tumor therapy. [ABSTRACT FROM AUTHOR]

Background: The tumor growth pattern in breast cancer appears to be variable and unpredictable. A minor increase in size in a pre-existing lesion, especially under 1 cm, corresponds to a more pronounced increase in volume. Case presentation: We report a 63-year-old woman with a nodular density mimicking intramammary lymph node, diagnosed as invasive carcinoma of luminal B subtype. The lesion increased size and density over time in following mammograms until having indistinct margins. While the tumor volume was 12.7 mm3 at the first observation on mammography, it has increased approximately 6.7 times to reach 85.7 mm3 in four years. Finally, the patient diagnosed with early-stage breast cancer (T1N0M0) was treated with breast-conserving surgery. Conclusions: Minor changes in size, density, and margin status of a lesion on serial mammograms are warning for breast cancer. Withal, a slight increase in lesion size in two dimensions can result in significant differences in volume. Therefore, comparative evaluation with previous mammograms and observing any difference in morphological features by screening are crucial for early diagnosis and optimal management of the disease. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the combined use of blood-based 3-protein signature and breast ultrasound (US) for validating US-detected lesions. Methods: From July 2011 to April 2020, women who underwent whole-breast US within at least 6 months from sampling period were retrospectively included. Blood-based 3-protein signature (Mastocheck®) value and US findings were evaluated. Following outcome measures were compared between US alone and the combination of Mastocheck® value with US: sensitivity, specificity, positive predictive value (PPV), negative predictive value, area under the receiver operating characteristic curve (AUC), and biopsy rate. Results: Among the 237 women included, 59 (24.9%) were healthy individuals and 178 (75.1%) cancer patients. Mean size of cancers was 1.2 ± 0.8 cm. Median value of Mastocheck® was significantly different between nonmalignant (− 0.24, interquartile range [IQR] − 0.48, − 0.03) and malignant lesions (0.55, IQR − 0.03, 1.42) (P <.001). Utilizing Mastocheck® value with US increased the AUC from 0.67 (95% confidence interval [CI] 0.61, 0.73) to 0.81 (95% CI 0.75, 0.88; P <.001), and specificity from 35.6 (95% CI 23.4, 47.8) to 64.4% (95% CI 52.2, 76.6; P <.001) without loss in sensitivity. PPV was increased from 82.2 (95% CI 77.1, 87.3) to 89.3% (95% CI 85.0, 93.6; P <.001), and biopsy rate was significantly decreased from 79.3 (188/237) to 72.1% (171/237) (P <.001). Consistent improvements in specificity, PPV, and AUC were observed in asymptomatic women, in women with dense breast, and in those with normal/benign mammographic findings. Conclusion: Mastocheck® is an effective tool that can be used with US to improve diagnostic specificity and reduce false-positive findings and unnecessary biopsies. [ABSTRACT FROM AUTHOR]

Breast cancer is classified into four major molecular subtypes, and is considered a heterogenous disease. The risk profiles and treatment of breast cancer differ according to these subtypes. Early detection dramatically improves the prospects of successful treatment, resulting in a reduction in overall mortality rates. However, almost 30% of women primarily diagnosed with the early-stage disease will eventually develop metastasis or resistance to chemotherapies. Immunotherapies are among the most promising cancer treatment options; however, long-term clinical benefit has only been observed in a small subset of responding patients. The current strategies for diagnosis and treatment rely heavily on histopathological examination and molecular diagnosis, disregarding the tumor microenvironment and microbiome involving cancer cells. In this review, we aim to praise the use of pharmacogenomics and pharmacomicrobiomics as a strategy to identify potential biomarkers for guiding and monitoring therapy in real-time. The finding of these biomarkers can be performed by studying the metabolism of drugs, more specifically, immunometabolism, and its relationship with the microbiome, without neglecting the information provided by genetics. A larger understanding of cancer biology has the potential to improve patient care, enable clinical decisions, and deliver personalized medicine. [ABSTRACT FROM AUTHOR]

The goal of this study was to describe the variation in hospital-based diagnostic care activities for patients with symptomatology suspect for breast cancer in The Netherlands. Two cohorts were included: the 'benign' cohort (30,334 women suspected of, but without breast cancer) and the 'malignant' cohort (2236 breast cancer patients). Hospital-based financial data was combined with tumor data (malignant cohort) from The Netherlands Cancer Registry. Patterns within diagnostic pathways were analyzed. Factors influencing the number of visits and number of diagnostic care activities until diagnosis were identified in the malignant cohort with multivariable Cox and Poisson regression models. Compared to patients with benign diagnosis, patients with malignant disease received their diagnosis less frequently in one day, after an equal average number of hospital visits and higher average number of diagnostic activities. Factors increasing the number of diagnostic care activities were the following: lower age and higher cM-and cN-stages. Factors increasing the number of days until (malignant) diagnosis were as follows: higher BIRADS-score, screen-detected and higher cN-and cT-stages. Hospital of diagnosis influenced both number of activities and days to diagnosis. The diagnostic care pathway of patients with malignant disease required more time and diagnostic activities than benign disease and depends on hospital, tumor and patient characteristics. [ABSTRACT FROM AUTHOR]