Approach For Treatment Of Breast Cancer Research Articles

Evaluation and comparison of different breast cancer prognosis scores based on gene expression data

BackgroundBreast cancer is one of the three most common cancers worldwide and is the most common malignancy in women. Treatment approaches for breast cancer are diverse and varied. Clinicians must balance risks and benefits when deciding treatments, and models have been developed to support this decision-making. Genomic risk scores (GRSs) may offer greater clinical value than standard clinicopathological models, but there is limited evidence as to whether these models perform better than the current clinical standard of care.MethodsPREDICT and GRSs were adapted using data from the original papers. Univariable Cox proportional hazards models were produced with breast cancer-specific survival (BCSS) as the outcome. Independent predictors of BCSS were used to build multivariable models with PREDICT. Signatures which provided independent prognostic information in multivariable models were incorporated into the PREDICT algorithm and assessed for calibration, discrimination and reclassification.ResultsEndoPredict, MammaPrint and Prosigna demonstrated prognostic power independent of PREDICT in multivariable models for ER-positive patients; no score predicted BCSS in ER-negative patients. Incorporating these models into PREDICT had only a modest impact upon calibration (with absolute improvements of 0.2–0.8%), discrimination (with no statistically significant c-index improvements) and reclassification (with 4–10% of patients being reclassified).ConclusionAddition of GRSs to PREDICT had limited impact on model fit or treatment received. This analysis does not support widespread adoption of current GRSs based on our implementations of commercial products.

The optimal regional irradiation volume for breast cancer patients: A comprehensive systematic review and network meta-analysis of published studies.

Currently, the optimal adjuvant regional nodal irradiation (RNI) volume for breast cancer (BC) remained controversial. We aimed to define the optimal RNI treatment volume for BC by using a comprehensive network meta-analysis (NMA) of published studies. PubMed, Embase, Medline, and Cochrane Central Register of Controlled Trials were searched from database inception to 30 May 2022. Studies assessing different adjuvant RNI volumes for BC were eligible for inclusion. The primary outcome was overall survival (OS), and secondary outcome was disease-free survival (DFS) and distant-metastasis-free survival (DMFS). A total of 29,640 BC patients from twenty studies were included. The pooled hazard ratio demonstrated that internal mammary node irradiation (IMNI) in BC patients significantly improved OS giving HR (hazard ratio) of 0.87 (95%CI: 0.83-0.91, p<0.001), DFS with HR of 0.78 (95%CI: 0.68-0.90, p<0.01), and DMFS with HR of 0.87 (95%CI: 0.79-0.97, p<0.01) when compared to controls. Sub-group analysis indicated that RNI with IMNI significantly improved OS (HR 0.87, 95%CI: 0.81-0.93, p<0.01), DFS (HR 0.65, 95%CI: 0.56-0.77, p<0.01), and DMFS (HR 0.90, 95%CI: 0.82-0.98, p=0.02) when compared to RNI without IMNI. NMA showed that CW/WB (chest wall/whole breast) + RNI with IMNI significantly improved DFS (HR 0.93, 95%CI: 0.86-1.00) and DMFS (HR 0.90, 95%CI: 0.81-0.99), but not for OS (HR 0.93, 95%CI: 0.84-1.03) when compared to CW/WB alone. Based on the analysis of the treatment ranking, CW/WB+RNI with IMNI appeared as the best treatment approach for BC patients. Our pooled results demonstrated that RNI with IMNI yielded a significant survival advantage for BC patients. NMA showed that CW/WB+RNI with IMNI was the optimal radiation volume for BC patients.

Therapeutic significance of molecular hybrids for breast cancer research and treatment.

Worldwide, breast cancer is still a leading cause of cancer death in women. Indeed, over the years, several anti-breast cancer drugs have been developed; however, the complex heterogeneous nature of breast cancer disease reduces the applicability of conventional targeted therapies with the upsurge in side effects and multi-drug resistance. Molecular hybrids generated by a combination of two or more active pharmacophores emerged as a promising approach in recent years for the design and synthesis of anti-breast cancer drugs. The hybrid anti-breast cancer molecules are well known for their several advantages compared to the parent moiety. These hybrid forms of anti-breast cancer molecules demonstrated remarkable effects in blocking different pathways contributing to the pathogenies of breast cancer and improved specificity. In addition, these hybrids are patient compliant with reduced side effects and multi-drug resistance. The literature revealed that molecular hybrids are applied to discover and develop novel hybrids for various complex diseases. This review article highlights the recent progress (∼2018-2022) in developing molecular hybrids, including linked, merged, and fused hybrids, as promising anti-breast cancer agents. Furthermore, their design principles, biological potential, and future perspective are discussed. The provided information will lead to the development of novel anti-breast cancer hybrids with excellent pharmacological profiles in the future.

Dual-Enhanced Pluronic Nanoformulated Methotrexate-Based Treatment Approach for Breast Cancer: Development and Evaluation of In Vitro and In Vivo Efficiency.

Breast cancer is a prevalent tumor and causes deadly metastatic complications. Myriad cancer types, including breast cancer, are effectively treated by methotrexate (MTX). However, MTX hydrophobicity, adverse effects and the development of resistance have inspired a search for new effective strategies to overcome these challenges. These may include the addition of a bioenhancer and/or encapsulation into appropriate nano-based carriers. In the present study, the anticancer effect of MTX was fortified through dual approaches. First, the concomitant use of piperine (PIP) as a bioenhancer with MTX, which was investigated in the MCF-7 cell line. The results depicted significantly lower IC50 values for the combination (PIP/MTX) than for MTX. Second, PIP and MTX were individually nanoformulated into F-127 pluronic nanomicelles (PIP-NMs) and F-127/P-105 mixed pluronic nanomicelles (MTX-MNMs), respectively, validated by several characterization techniques, and the re-investigated cytotoxicity of PIP-NMs and MTX-MNMs was fortified. Besides, the PIP-NMs/MTX-MNMs demonstrated further cytotoxicity enhancement. The PIP-NMs/MTX-MNMs combination was analyzed by flow cytometry to understand the cell death mechanism. Moreover, the in vivo assessment of PIP-NMs/MTX-MNMs was adopted through the Ehrlich ascites model, which revealed a significant reduction of the tumor weight. However, some results of the tumor markers showed that the addition of PIP-NMs to MTX-MNMs did not significantly enhance the antitumor effect.

Breast cancer in the era of precision medicine.

Breast cancer is a heterogeneous disorder with different molecular subtypes and biological characteristics for which there are diverse therapeutic approaches and clinical outcomes specific to any molecular subtype. It is a global health concern due to a lack of efficient therapy regimens that might be used for all disease subtypes. Therefore, treatment customization for each patient depending on molecular characteristics should be considered. Precision medicine for breast cancer is an approach to diagnosis, treatment, and prevention of the disease that takes into consideration the patient's genetic makeup. Precision medicine provides the promise of highly individualized treatment, in which each individual breast cancer patient receives the most appropriate diagnostics and targeted therapies based on the genetic profile of cancer. The knowledge about the molecular features and development of breast cancer treatment approaches has increased, which led to the development of new targeted therapeutics. Tumor genomic profiling is the standard of care for breast cancer that could contribute to taking steps to better management of malignancies. It holds great promise for accurate prognostication, prediction of response to common systemic therapies, and individualized monitoring of the disease. The emergence of targeted treatment has significantly enhanced the survival of patients with breast cancer and contributed to reducing the economic costs of the health system. In this review, we summarized the therapeutic approaches associated with the molecular classification of breast cancer to help the best treatment selection specific to the target patient.

Heme Oxygenase Modulation Drives Ferroptosis in TNBC Cells.

The term ferroptosis refers to a peculiar type of programmed cell death (PCD) mainly characterized by extensive iron-dependent lipid peroxidation. Recently, ferroptosis has been suggested as a potential new strategy for the treatment of several cancers, including breast cancer (BC). In particular, among the BC subtypes, triple negative breast cancer (TNBC) is considered the most aggressive, and conventional drugs fail to provide long-term efficacy. In this context, our study’s purpose was to investigate the mechanism of ferroptosis in breast cancer cell lines and reveal the significance of heme oxygenase (HO) modulation in the process, providing new biochemical approaches. HO’s effect on BC was evaluated by MTT tests, gene silencing, Western blot analysis, and measurement of reactive oxygen species (ROS), glutathione (GSH) and lipid hydroperoxide (LOOH) levels. In order to assess HO’s implication, different approaches were exploited, using two distinct HO-1 inducers (hemin and curcumin), a well-known HO inhibitor (SnMP) and a selective HO-2 inhibitor. The data obtained showed HO’s contribution to the onset of ferroptosis; in particular, HO-1 induction seemed to accelerate the process. Moreover, our results suggest a potential role of HO-2 in erastin-induced ferroptosis. In view of the above, HO modulation in ferroptosis can offer a novel approach for breast cancer treatment.

Abstract P1-08-33: Disparities in the practice of precision medicine? Using multi-gene testing in early-stage, HR+/HER2- breast cancer

Abstract Background: Multi-gene testing (MGT) can be used to identify patients with early-stage, hormone receptor-positive (HR+), HER2-negative (HER2-) breast cancer that are likely to benefit from treatment regimens with chemotherapy and endocrine therapy, compared to endocrine therapy alone. Two examples of genomic panels include OncotypeDX (ODX) MammaPrint (MP). Tailoring practice to the unique profile of each patient, known as ‘precision medicine’, has significantly refined the treatment approach in breast cancer, while decreasing toxicity and cost. In this analysis, we explore disparities in the access to precision medicine among several socio-demographic groups. Methods: We conducted a retrospective analysis of the National Cancer Database, using the 2004-2017 breast cancer dataset. We included patients with HR+/HER2-, stage I-II breast cancer. We excluded patients with stage III disease as many would still receive chemotherapy with less use of MGT. Using chi-squared statistics, we identified socio-demographic, clinical and pathologic factors associated with the use MGT - either ODX or MP - in this group. We then included significant variables (p&amp;lt;0.05) in one multiple logistic regression model predicting the use of either genomic panel. Results: A total of n=841,716 patients who were candidates for MGT (early-stage, HR+/HER2- breast cancer) were included in this analysis. N=283,833 (n=33.7%) underwent MGT (32.2% used ODX while 1.5% used MP). Use of genomic assays has increased significantly over time (11.5% for patients diagnosed between 2007-2009, to 39.4% between 2016-2017). Variables significantly associated with the use of either ODX/MP at the multivariate level (p&amp;lt;0.05) included: age, race, insurance status, education level, facility type, year of diagnosis, geographic location, tumor grade, and tumor histology. Elderly patients (&amp;gt;70) were less likely than those &amp;lt;50 to undergo MGT (OR 0.32, 95% CI 0.32-0.33, p&amp;lt;0.001). Black patients were also less likely to receive a genomic assay compared to White patients (OR 0.80, 95% CI 0.78-0.82, p&amp;lt;0.001). Insurance status was another significant predictor, with uninsured patients being the least likely to receive ODX or MP (OR 0.69, 95% CI 0.66-0.72, p&amp;lt;0.001), compared to those with private insurance. Conversely, patients treated at academic/research cancer programs were more likely to undergo MGT than those treated at community cancer programs (OR 1.13, 95% CI 1.10-1.15, p&amp;lt;0.001). Geographic discordance in use of MGT was also identified: with highest rates of use (39.2%) in the Middle Atlantic (NJ, NY, PA), and lowest rates (23.5%) in West South-Central states (AR, LA, OK, TX). Conclusions: This large analysis of real world, national data identified several social determinants of health predictive of disparity in the implementation of precision medicine practices for early-stage, HR+/HER2- breast cancer. Improving access to innovative, diagnostic and prognostic tools, among black and underinsured patients, as well as those treated in community practices, is needed. Citation Format: Nadeem Bilani, Marita Yaghi, Diana Saravia, Iktej Jabbal, Maroun Bou Zerdan, Leah Elson, Liang Hong, Zeina Nahleh. Disparities in the practice of precision medicine? Using multi-gene testing in early-stage, HR+/HER2- breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-08-33.

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX–PPARγ axis can be considered a novel approach for breast cancer treatment.

KCNQ1OT1 affects cell proliferation, invasion, and migration through a miR-34a / Notch3 axis in breast cancer.

Breast cancer (BC) accounts for a significant share of cancer-related deaths worldwide. Ongoing investigations have shown that long non-coding RNAs (lncRNAs) drive BC progression but their underlying mechanisms remain largely undescribed. LncRNA KCNQ1OT1 was previously identified in BC but its functional significance remained to be fully investigated. KCNQ1OT1 and its downstream target genes were analyzed in breast cancer tissues and cell lines using methods including RT-qPCR, immunohistochemistry and Western blotting. The effects of KCNQ1OT1, miR-34a and Notch3 on BC cells were investigated using assays measuring proliferation (CCK-8, colony formation), apoptosis, and migration/invasion (scratch and Transwell assays). MS2-RIP and dual-luciferase reporter assays were used to study RNA interactions. Xenograft studies were employed to define the tumorigenic potential of KCNQ1OT1 in vivo. KCNQ1OT1 expression was up-regulated in BC tissues and high levels were associated with poorer prognosis. ShRNA inhibition of KCNQ1OT1 expression in BC cell lines retarded proliferation, migration and invasion in vitro and tumor growth in vivo. Up-regulation of KCNQ1OT1 was shown to inhibit miR-34a which was associated with blocking the inhibitory effect of miR-34a on BC cell proliferation, migration and invasion. Notch3 was found to be a downstream target of miR-34a with KCNQ1OT1 markedly inducing Notch3 expression in BC. Evidence for KCNQ1OT1/miR-34a/Notch3 axis was further established in clinical BC samples. We identified a KCNQ1OT1/miR-34a/Notch3 axis which promotes BC progression through effects on cell proliferation and metastasis that was further associated with poor patient prognosis. These results propose targeting this axis as novel treatment approach for BC.

The Role of Rosmarinic Acid on the Bioproduction of Gold Nanoparticles as Part of a Photothermal Approach for Breast Cancer Treatment.

Breast cancer is a high-burden malignancy for society, whose impact boosts a continuous search for novel diagnostic and therapeutic tools. Among the recent therapeutic approaches, photothermal therapy (PTT), which causes tumor cell death by hyperthermia after being irradiated with a light source, represents a high-potential strategy. Furthermore, the effectiveness of PTT can be improved by combining near infrared (NIR) irradiation with gold nanoparticles (AuNPs) as photothermal enhancers. Herein, an alternative synthetic method using rosmarinic acid (RA) for synthesizing AuNPs is reported. The RA concentration was varied and its impact on the AuNPs physicochemical and optical features was assessed. Results showed that RA concentration plays an active role on AuNPs features, allowing the optimization of mean size and maximum absorbance peak. Moreover, the synthetic method explored here allowed us to obtain negatively charged AuNPs with sizes favoring the local particle accumulation at tumor site and maximum absorbance peaks within the NIR region. In addition, AuNPs were safe both in vitro and in vivo. In conclusion, the synthesized AuNPs present favorable properties to be applied as part of a PTT system combining AuNPs with a NIR laser for the treatment of breast cancer.

Using Nanotechnology for Diagnosis and Treatment of Breast Cancer: A Review

One of the leading causes of death in women around the word is breast cancer. For the treatment of most cancers, chemotherapy is a good option. The most treatment approaches for breast cancer are radiotherapy, surgery and chemotherapy. There are some restrictions and limitations in diagnostic approaches and treatment methods. They result in the progress of new diagnosis and treatment approaches to improve the life quality of patients. Application of nanotechnology in the treatment of cancers currently has received much attention. In cancer treatments, nanotechnology plays a significant role in the drug delivery. Tumors can be targeted by nanoparticles. They have important role in controlling the drug release to accurate sites. Therefore, nanoparticles improve the drug efficiency and reduce the normal organ’s toxicity. Another ability of nanoparticles is activation of immune cells against tumors. As a result, nanoparticles can be used as a proper and efficient tool in the treatment and diagnosis of cancer. In this review we discuss about using nanotechnology and application of different nanoparticles in diagnosis and treatment of breast cancer.

Gene therapy: A promising approach for breast cancer treatment

Breast cancer (BC) is the most prevalent malignancy and the second leading cause of death among women worldwide that is caused by numerous genetic and environmental factors. Hence, effective treatment for this type of cancer requires new therapeutic approaches. The traditional methods for treating this cancer have side effects, therefore so much research have been performed in last decade to find new methods to alleviate these problems. The study of the molecular basis of breast cancer has led to the introduction of gene therapy as an effective therapeutic approach for this cancer. Gene therapy involves sending genetic material through a vector into target cells, which is followed by a correction, addition, or suppression of the gene. In this technique, it is necessary to target tumour cells without affecting normal cells. In addition, clinical trial studies have shown that this approach is less toxic than traditional therapies. This study will review various aspects of breast cancer, gene therapy strategies, limitations, challenges and recent studies in this area.

Recombinant adeno-associated viruses as a gene delivery vehicle for the use in molecular medicine

Breast cancer (BC) is a cancer with a high prevalence and mortality among women worldwide. With the current diagnostics methods, BC may remain undetected at its early stages, and the therapies developed for the disease are associated with severe side effects. Oncolytic viruses can be the basis of the new, effective BC treatment approaches. The viruses destroy tumor cells directly and launch the antitumor immune response; this dual action supports their efficacy. It is possible to make the oncolytic virus therapy more effective by designing genetically modified viruses that can target BC cells better and/or induce a stronger antitumor immune response. This review outlines the directions of development of oncolytic viruses in BC treatment, covers the optimal ways of delivering viruses to the tumor and the efficacy of their use in combination with other therapeutic agents (methods) and presents the prospects of using oncolytic viruses in antitumor vaccines.

Nanotechnology to Cure Breast Cancer and Obstacles in its Way

Nanomaterials owing to their remarkable pharmaceutical properties and potential to load large quantities of drugs are considered an ideal vector for carrying medicine to the target site. The treatment of breast cancer has been a pressing issue due the use of conventional methods of treatment resulting in many side effects. Nanotechnology offers a more targeted approach in breast cancer treatment. The present review examines the role of Carbon Nanotubes (CNTs) and nanoparticles in the treatment of breast cancer and the obstacles in the way of nanotechnology in becoming one of the best methods in breast cancer treatment and drug delivery. Use of monoclonal antibody trastuzumab against HER-2 biomarkers by attaching it with nanotubes or nanoparticles is considered the best-targeted therapy along with photo thermal ablation. The absence of human tumor models and lack of toxicological assays are the major factors contributing to differences between the preclinical and clinical trial results.

227P Risk of breast cancer understaging through standard clinical and radiographic staging in Botswana

An accurate staging is essential to determine the optimal treatment approach for breast cancer. In resource-limited settings, breast cancer staging relies on physical examination, a frontal chest radiograph, abdominal ultrasound and blood chemistries. Our understanding of the performance of this standard clinical and radiographic staging in sub-Saharan Africa is limited.

Azadiradione-loaded liposomes with improved bioavailability and anticancer efficacy against triple negative breast cancer

Triple negative breast cancer (TNBC) is the most aggressive subtype of the breast cancer commonly occurring in females. It was estimated that around 17%–25% of people with breast cancer are triple negative. Despite the availability of various therapeutics and approaches for breast cancer treatment, there is still an increasing need to develop safe and efficacious agents for cancer therapy. Azadiradione (AZD), a bioactive agent isolated from Azadiractaindica, is known to possess anti-nociceptive and anti-inflammatory activities. However, AZD use is limited due to its poor bioavailability. In the current study, the bioavailability of AZD-loaded liposomes in mice was investigated. The anticancer efficacy of AZD-loaded liposomes against TNBC cell line (MDA-MB-231) was also assessed. Data have shown that the oral bioavailability of AZD from liposomes was significantly higher in comparison to free AZD. Also, the anticancer activity of AZD-loaded liposomes against TNBC cells in vitro was markedly enhanced and was found to be via down regulation of the proteins required for proliferation, survival and angiogenesis such as cyclin D1, COX-2, survivin, VEGF-A and autophagy. In conclusion, this study suggested that AZD-loaded liposomes might be a potential oral delivery system to improve bioavailability and hence, therapeutic efficacy of AZD. However, further surface modification of AZD liposomes via PEGylation is required to increase drug blood circulation and reduce phagocytosis and uptake by RES.

Targeting of FK506 binding protein 5 by miR-203 affects the progression of breast cancer via regulating the fatty acid degradation pathway and potential drug-repurposing.

Increasing number of studies have suggested that microRNA (miR)-203 is a potential prognostic marker for breast cancer. However, the specific molecular mechanism underlying the effects of miR-203 remains unknown. The present study aimed to explore the molecular target and underlying mechanisms of action of miR-203 in breast cancer via bioinformatics analysis and cellular assays, such as wound healing assay and western blotting. In the present study, 17 candidate target genes of miR-203 were identified in the downregulated differentially expressed genes from Affymetrix microarray and TargetScan 7.2 database. Subsequently, FK506 binding protein 5 (FKBP5) was considered as the miR-203 target by 3 different hub gene analysis methods (EcCentricity, Betweenness and Stress). FKBP5 protein expression was significantly downregulated in SUM159 cells transfected with miR-203 mimics compared with SUM159 cells transfected with miR-203 negative control (NC) in western blot analysis. High expression of FKBP5 was associated with poor prognosis in breast cancer based on the results obtained from the Kaplan-Meier Plotter database. In addition, the wound healing assay indicated that the inhibition of migration due to miR-203 overexpression in SUM159 cells was reversed by FKBP5 overexpression. These results suggested that miR-203 may directly target FKBP5. In addition, Gene Set Enrichment Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that miR-203 might play a role in breast cancer via the ‘fatty acid degradation’ KEGG pathway. Notably, the levels of fatty acids were significantly reduced in SUM159 cells transfected with miR-203 mimics compared with SUM159 cells transfected with miR-203 NC when assessed by the fatty acid content assay. Finally, virtual screening analysis revealed that ZINC000003944422 may be a potential inhibitor of FKBP5. In summary, the present study demonstrated that miR-203 may directly target FKBP5 in breast cancer via fatty acid degradation and potential drugs, hence providing a novel treatment approach for breast cancer.

Preparation, Optimization and In-Vitro Evaluation of Curcumin-Loaded Niosome@calcium Alginate Nanocarrier as a New Approach for Breast Cancer Treatment.

Simple SummaryWe provided an effective approach for the treatment of breast cancer as a malignant disease. Regards to this, we used drug delivery system. This approach does not have any side effects on the patients who suffer from cancer unlike chemotherapy, radiotherapy and drug resistance. This system implicates on using nano-drugs which loaded into nano-carrier. During this study, we used niosome@calcium alginate as a nano carrier which contained curcumin in aim of eradicating breast cancer cell lines. Through the research, we applied the above mentioned sample to breast cancer cell lines that were SKBR3 and MDA-MB231 and measured gene expression level to evaluate efficacy of this novel approach in therapy of this disease. Interestingly, applying curcumin loaded into niosome@calcium alginate in SKBR3 and MDA-MB231 as a treatment enhances cancer cell’s death and apoptosis. We hope that this method could use as an effective and novel manner for the treatment of breast cancer. Cancer is one of the most common causes of mortality, and its various treatment methods can have many challenges for patients. As one of the most widely used cancer treatments, chemotherapy may result in diverse side effects. The lack of targeted drug delivery to tumor tissues can raise the possibility of damage to healthy tissues, with attendant dysfunction. In the present study, an optimum formulation of curcumin-loaded niosomes with a calcium alginate shell (AL-NioC) was developed and optimized by a three-level Box–Behnken design—in terms of dimension and drug loading efficiency. The niosomes were characterized by transmission electron microscopy, Fourier-transform infrared spectroscopy, and dynamic light scattering. The as-formulated niosomes showed excellent stability for up to 1 month at 4 °C. Additionally, the niosomal formulation demonstrated a pH-dependent release; a slow-release profile in physiological pH (7.4), and a more significant release rate at acidic conditions (pH = 3). Cytotoxicity studies showed high compatibility of AL-NioC toward normal MCF10A cells, while significant toxicity was observed in MDA-MB-231 and SKBR3 breast cancer cells. Gene expression studies of the cancer cells showed downregulation of Bcl2, cyclin D, and cyclin E genes, as well as upregulation of P53, Bax, caspase-3, and caspase-9 genes expression following the designed treatment. Flow cytometry studies confirmed a significant enhancement in the apoptosis rate in the presence of AL-NioC in both MDA-MB-231 and SKBR3 cells as compared to other samples. In general, the results of this study demonstrated that—thanks to its biocompatibility toward normal cells—the AL-NioC formulation can efficiently deliver hydrophobic drugs to target cancer cells while reducing side effects.

LOXL2 Inhibitors and Breast Cancer Progression.

LOX (lysyl oxidase) and lysyl oxidase like-1–4 (LOXL 1–4) are amine oxidases, which catalyze cross-linking reactions of elastin and collagen in the connective tissue. These amine oxidases also allow the cross-link of collagen and elastin in the extracellular matrix of tumors, facilitating the process of cell migration and the formation of metastases. LOXL2 is of particular interest in cancer biology as it is highly expressed in some tumors. This protein also promotes oncogenic transformation and affects the proliferation of breast cancer cells. LOX and LOXL2 inhibition have thus been suggested as a promising strategy to prevent metastasis and invasion of breast cancer. BAPN (β-aminopropionitrile) was the first compound described as a LOX inhibitor and was obtained from a natural source. However, novel synthetic compounds that act as LOX/LOXL2 selective inhibitors or as dual LOX/LOX-L inhibitors have been recently developed. In this review, we describe LOX enzymes and their role in promoting cancer development and metastases, with a special focus on LOXL2 and breast cancer progression. Moreover, the recent advances in the development of LOXL2 inhibitors are also addressed. Overall, this work contextualizes and explores the importance of LOXL2 inhibition as a promising novel complementary and effective therapeutic approach for breast cancer treatment.

PPARα-Selective Antagonist GW6471 Inhibits Cell Growth in Breast Cancer Stem Cells Inducing Energy Imbalance and Metabolic Stress.

Breast cancer is the most frequent cancer and the second leading cause of death among women. Triple-negative breast cancer is the most aggressive subtype of breast cancer and is characterized by the absence of hormone receptors and human epithelial growth factor receptor 2. Cancer stem cells (CSCs) represent a small population of tumor cells showing a crucial role in tumor progression, metastasis, recurrence, and drug resistance. The presence of CSCs can explain the failure of conventional therapies to completely eradicate cancer. Thus, to overcome this limit, targeting CSCs may constitute a promising approach for breast cancer treatment, especially in the triple-negative form. To this purpose, we isolated and characterized breast cancer stem cells from a triple-negative breast cancer cell line, MDA-MB-231. The obtained mammospheres were then treated with the specific PPARα antagonist GW6471, after which, glucose, lipid metabolism, and invasiveness were analyzed. Notably, GW6471 reduced cancer stem cell viability, proliferation, and spheroid formation, leading to apoptosis and metabolic impairment. Overall, our findings suggest that GW6471 may be used as a potent adjuvant for gold standard therapies for triple-negative breast cancer, opening the possibility for preclinical and clinical trials for this class of compounds.