Androgens Modulate Bcl-2 Agonist of Cell Death (BAD) Expression and Function in Breast Cancer Cells.

Androgen receptor (AR) expression in estrogen receptor-positive (ER+) breast cancer (BC) correlates with lower tumor grade and a better clinical outcome. Additionally, in normal mammary epithelium or ER+ BC preclinical models, androgens counteract basal/ER-dependent proliferation. Here, we report an additional mechanism, underlining the protective role exerted by AR. Specifically, the activation of intracellular AR upregulates the Bcl-2-family protein BAD, and TCGA database analyses show that in ER+ BC, BAD expression is associated with better disease-free survival. Ligand-activated AR influences its own and BAD cellular compartmentalization by enhancing levels in the nucleus, as well as in mitochondrial fractions. In both compartments, BAD exerts unconventional functions. In the nucleus, BAD and AR physically interact and, upon androgen stimulation, are recruited at the AP-1 and ARE sites within the cyclin D1 promoter region, contributing to explaining the anti-proliferative effect of androgens in BC cells. Androgens cause an enrichment in BAD and AR content in the mitochondria, correlated with a decrease in mitochondrial function. Thus, we have defined a novel mechanism by which androgens modulate BAD expression, its mitochondria localization, and nuclear content to force its ability to act as a cell cycle inhibitor, strengthening the protective role of androgen signaling in estrogen-responsive BCs.

Hybrid Polymer-Silica Nanostructured Materials for Environmental Remediation.

Due to the ever-growing global population, it is necessary to develop highly effective processes that minimize the impact of human activities and consumption on the environment. The levels of organic and inorganic contaminants have rapidly increased in recent years, posing a threat to ecosystems. Removing these toxic pollutants from the environment is a challenging task that requires physical, chemical, and biological methods. An effective solution involves the use of novel engineered materials, such as silica-based nanostructured materials, which exhibit a high removal capacity for various pollutants. The starting materials are also thermally and mechanically stable, allowing for easy design and development at the nanoscale through versatile functionalization procedures, enabling their effective use in pollutant capture. However, improvements concerning mechanical properties or applicability for repeated cycles may be required to refine their structural features. This review focuses on hybrid/composite polymer-silica nanostructured materials. The state of the art in nanomaterial synthesis, different techniques of functionalization, and polymer grafting are described. Furthermore, it explores the application of polymer-modified nanostructured materials for the capture of heavy metals, dyes, hydrocarbons and petroleum derivatives, drugs, and other organic compounds. The paper concludes by offering recommendations for future research aimed at advancing the application of polymer-silica nanostructured materials in the efficiency of pollutant uptake.

LPL, FNDC5 and PPARγ gene polymorphisms related to body composition parameters and lipid metabolic profile in adolescents from Southern Italy.

BACKGROUND: Plasma lipid profile and anthropometric variables are known to be under strong genetic control and the identification of genetic variants associated with bioclinical parameters is of considerable public health importance. In this study, a young cohort of healthy individuals was genotyped for genes related to health and pathological conditions, to analyze the association of single nucleotide polymorphisms (SNPs) with different bioclinical parameters, adherence to the Mediterranean Diet (MD) and physical activity, studying the role of lifestyle and body composition parameters on biochemical metabolic profile. METHODS: Association analysis of single variants in the genes of lipoprotein lipase (LPL), fibronectin type III domain containing protein 5 (FNDC5), and peroxisome proliferator-activated receptor-gamma (PPARγ) and haplotype analyses were performed. RESULTS: Multiple (n = 14) common variants in the three genes demonstrated a significant effect on plasma lipoprotein-lipid levels and/or on biochemical parameters in our sample. Specifically, SNPs were related to lipid metabolism (rs3866471, rs4922115, rs11570892, rs248, rs316, rs1059507, rs1801282) or glycemic profile (rs3208305) or anthropometric parameters (rs3480, rs726344, rs1570569) for a total of 26 significant associations (P < 0.01 and/or P < 0.05) and two haplotypes, for the first time, were strongly associated with lipid and body composition parameters. Interestingly, we identified twenty-four new variants not previously described in the literature and a novel significant association between rs80143795 and body composition. CONCLUSIONS: In this study we confirm the association between these SNPs on lipid metabolism and body parameters also in a young cohort, indicating the important role of these genetic factors as determinants of health.

The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.

Adherence to the Mediterranean diet pattern among university staff: a cross-sectional web-based epidemiological study in Southern Italy.

In this cross-sectional web-survey, carried out in 340 employees (24-67 years) among university staff of Southern Italy, we assessed the adherence to the Mediterranean Diet (MD). Using an online questionnaire based on validated 14-point MD Adherence Screener (MEDAS), the mean of the score was 7.34 (±1.9) for total population independently of sex. In population divided by the cut-off age of 45 years, MD adherence resulted significantly lower in younger respect to older group (p = .003). In multiple regression analyses we observed the direct association between MEDAS score and older age group also after adjustments. Importantly, in all sample the percentage of adherers to recommendations for fruits, nuts and fish resulted outside dietary guidelines. The present findings underscore the need to develop healthy education programmes aimed to improve the consumption of several components of the MD, particularly among young adults, in order to prevent the early onset of chronic non-transmittable diseases.

Evidence for Enhanced Exosome Production in Aromatase Inhibitor-Resistant Breast Cancer Cells.

Aromatase inhibitors (AIs) represent the standard anti-hormonal therapy for post-menopausal estrogen receptor-positive breast cancer, but their efficacy is limited by the emergence of AI resistance (AIR). Exosomes act as vehicles to engender cancer progression and drug resistance. The goal of this work was to study exosome contribution in AIR mechanisms, using estrogen-dependent MCF-7 breast cancer cells as models and MCF-7 LTED (Long-Term Estrogen Deprived) subline, modeling AIR. We found that exosome secretion was significantly increased in MCF-7 LTED cells compared to MCF-7 cells. MCF-7 LTED cells also exhibited a higher amount of exosomal RNA and proteins than MCF-7 cells. Proteomic analysis revealed significant alterations in the cellular proteome. Indeed, we showed an enrichment of proteins frequently identified in exosomes in MCF-7 LTED cells. The most up-regulated proteins in MCF-7 LTED cells were represented by Rab GTPases, important vesicle transport-regulators in cancer, that are significantly mapped in "small GTPase-mediated signal transduction", "protein transport" and "vesicle-mediated transport" Gene Ontology categories. Expression of selected Rab GTPases was validated by immunoblotting. Collectively, we evidence, for the first time, that AIR breast cancer cells display an increased capability to release exosomes, which may be associated with an enhanced Rab GTPase expression. These data provide the rationale for further studies directed at clarifying exosome's role on endocrine therapy, with the aim to offer relevant markers and druggable therapeutic targets for the management of hormone-resistant breast cancers.

AIB1 sequestration by androgen receptor inhibits estrogen-dependent cyclin D1 expression in breast cancer cells.

BACKGROUND: Androgens, through their own receptor, play a protective role on breast tumor development and progression and counterbalance estrogen-dependent growth stimuli which are intimately linked to breast carcinogenesis. METHODS: Cell counting by trypan blu exclusion was used to study androgen effect on estrogen-dependent breast tumor growth. Quantitative Real Time RT-PCR, western blotting, transient transfection, protein immunoprecipitation and chromatin immunoprecipitation assays were carried out to investigate how androgen treatment and/or androgen receptor overexpression influences the functional interaction between the steroid receptor coactivator AIB1 and the estrogen- or androgen receptor which, in turn affects the estrogen-induced cyclin D1 gene expression in MCF-7 breast cancer cells. Data were analyzed by ANOVA. RESULTS: Here we demonstrated, in estrogen receptor α (ERα)-positive breast cancer cells, an androgen-dependent mechanism through which ligand-activated androgen receptor (AR) decreases estradiol-induced cyclin D1 protein, mRNA and gene promoter activity. These effects involve the competition between AR and ERα for the interaction with the steroid receptor coactivator AIB1, a limiting factor in the functional coupling of the ERα with the cyclin D1 promoter. Indeed, AIB1 overexpression is able to reverse the down-regulatory effects exerted by AR on ERα-mediated induction of cyclin D1 promoter activity. Co-immunoprecipitation studies indicated that the preferential interaction of AIB1 with ERα or AR depends on the intracellular expression levels of the two steroid receptors. In addition, ChIP analysis evidenced that androgen administration decreased E2-induced recruitment of AIB1 on the AP-1 site containing region of the cyclin D1 gene promoter. CONCLUSIONS: Taken together all these data support the hypothesis that AIB1 sequestration by AR may be an effective mechanism to explain the reduction of estrogen-induced cyclin D1 gene activity. In estrogen-dependent breast cancer cell proliferation, these findings reinforce the possibility that targeting AR signalling may potentiate the effectiveness of anti-estrogen adjuvant therapies.

Estradiol via estrogen receptor beta influences ROS levels through the transcriptional regulation of SIRT3 in human seminoma TCam-2 cells.

Human testis, gonocytes, and adult germ cells mainly express estrogen receptor beta, and estrogen receptor beta loss is associated with advanced tumor stage; however, the molecular mechanisms of estrogen receptor beta-protective effects are still to be defined. Herein, we provide evidence that in human seminoma TCam-2 cells, E2 through estrogen receptor beta upregulates the mitochondrial deacetylase sirtuin-3 at protein and messenger RNA levels. Specifically, E2 increases sirtuin-3 expression through a transcriptional mechanism due to the occupancy of sirtuin-3 promoter by estrogen receptor beta, together with the transcription factor Sp1 as evidenced by Chip reChIp assay. This complex binds to a GC cluster located between -128 bp/+1 bp and is fundamental for E2 effects, as demonstrated by Sp1 small interfering RNA studies. Beside, after 24 h, E2 stimulus significantly increased activities of superoxide dismutase and catalase to scavenge reactive oxygen species produced by 30 min of E2 stimulus. In summary, this article indicates a novel functional interplay between estrogen receptor beta and sirtuin-3 counteracting reactive oxygen species production in TCam-2 cells. Our findings thus show that an important tumor-suppressive pathway through estrogen receptor beta is target of E2, actually proposing a distinctive protecting action against seminoma. Future studies may lead to additional strategies for the current therapy of seminoma.

Bergapten drives autophagy through the up-regulation of PTEN expression in breast cancer cells.

BACKGROUND: Bergapten (5-methoxypsoralen), a natural psoralen derivative present in many fruits and vegetables, has shown antitumoral effects in a variety of cell types. In this study, it has been addressed how Bergapten in breast cancer cells induces autophagic process. RESULTS: In MCF7 and ZR-75 breast cancer cells Bergapten exhibited anti-survival response by inducing the autophagic process increasing Beclin1, PI3KIII, UVRAG, AMBRA expression and conversion of LC3-I to LC3-II. LC3-GFP, Acridine orange assay and transmission electron microscopy even confirmed the increased autophagosome formations in treated cells. Bergapten-induced autophagy is dependent by PTEN up-regulation, since silencing this gene, the induction of Beclin1 and the p-AKT/p-mTOR signal down-regulation were reversed. PTEN is transcriptionally regulated by Bergapten through the involvement of p38MAPK/NF-Y, as evidenced by the use of p38MAPK inhibitor SB203580, site-direct mutagenesis of NF-Y element and NF-Y siRNA. Furthermore NF-Y knockdown prevented Bergapten-induced acid vesicular organelle accumulations (AVOs), strengthening the role of this element in mediating autophagy. CONCLUSIONS: Our data indicate PTEN as a key target of Bergapten action in breast cancer cells for the induction of autophagy. These findings add further details on the mechanism of action of Bergapten, therefore suggesting that phytochemical compounds may be implemented in the novel strategies for breast cancer treatment.

Engineered Mesoporous Silica-Based Nanoparticles: Characterization of Surface Properties.

Mesoporous silica-based nanomaterials have emerged as multifunctional platforms with applications spanning catalysis, medicine, and nanotechnology. Since their synthesis in the early 1990s, these materials have attracted considerable interest due to their unique properties, including high surface area, tunable pore size, and customizable surface chemistry. This article explores the surface properties of a series of MSU-type mesoporous silica nanoparticles, elucidating the impact of different functionalization strategies on surface characteristics. Through an extensive characterization utilizing various techniques, such as FTIR, Z-potential, and nitrogen adsorption porosimetry, insights into the surface modifications of mesoporous silica nanoparticles are provided, contributing to a deeper understanding of their nanostructure and related interactions, and paving the way to possible unexpected actionability and potential applications.

Impact of COVID-19 Lockdown on Metabolic/Inflammatory Profile in Adolescents: Cellular Studies and Predictive Biomarkers.

CONTEXT: The COVID-19 pandemic and its lockdown restrictions changed people's lifestyles with potential negative impact on health. OBJECTIVE: This longitudinal study aimed to assess the COVID-19 lockdown influence on the adherence to the Mediterranean diet (MD) pattern and its effects on the metabolic inflammatory profile in a cohort of healthy adolescents. METHODS: We analyzed anthropometric measurements, body composition, and MD adherence along with serum metabolic and inflammatory profile in 77 healthy adolescents from southern Italy before and after the COVID-19 pandemic lockdown. Additionally, we evaluated the biological properties of prelockdown and postlockdown serum on human HepG2 and HuH-7 hepatic cells. RESULTS: We did not observe any significant differences in anthropometric and body composition parameters as well as MD adherence score in adolescents between prelockdown and postlockdown COVID-19. Intriguingly, although the metabolic profile of adolescents postlockdown was within the normal range, we evidenced increased levels of fasting glucose, triglycerides, total cholesterol, and low-density lipoprotein (LDL) along with a reduction in high-density lipoprotein (HDL) in postlockdown compared with prelockdown adolescent serum. In addition, elevated levels of tumor necrosis factor (TNF)-α, interleukin-1ß, and ferritin were found in postlockdown adolescents compared with their prelockdown counterparts. Consistent with the biochemical parameters, we observed enhanced lipid accumulation with altered mitochondrial functions and increased reactive oxygen species production in HepG2 and HuH-7 cells treated with pooled serum from postlockdown with respect to prelockdown period. Receiver operator characteristic curve analysis identified total cholesterol, LDL, HDL, TNF-α, and ferritin to be predictive serum markers for metabolic and inflammatory profiling after the lockdown period. CONCLUSION: Our findings highlight that the COVID-19 lockdown, forcing sedentary behavior, had a negative impact on adolescents' metabolic and inflammatory profile which may result in long-term poor health outcomes.

Red wine consumption may affect sperm biology: the effects of different concentrations of the phytoestrogen myricetin on human male gamete function.

Myricetin is a natural flavonoid, particularly enriched in red wines, whose occurrence is widespread among plants. Despite extensive research, the beneficial effects of Myricetin on human health are still controversial. Here, we tested the estrogen-like effect of the phytoestrogen Myricetin on human ejaculated sperm biology. To this aim, human normozoospermic samples were exposed to increasing concentrations (10 nM, 100 nM, and 1 µM) of Myricetin. Motility, viability, capacitation-associated biochemical changes (i.e., cholesterol efflux and tyrosine phosphorylation), acrosin activity, as well as glucose utilization and fatty-acid oxidation (i.e., glucose and lipid metabolism) were all significantly increased by low doses of Myricetin. Importantly, both estrogen receptors α and ß (ERs) and phosphatidylinositol-3-OH kinase (PI3K)/AKT signaling are activated in the presence of Myricetin since these were both abrogated by specific inhibitors of each pathway. Our results show how Myricetin, through ERs and PI3K/AKT signalings, potentiates sperm function. This effect is dose-dependent at low concentrations of Myricetin (up to 100 nM), whereas higher amounts do not seem to improve any further sperm motility, viability, or other tested features, and, in some cases, they reduced or even abrogated the efficacy exerted by lower doses. Further studies are needed to elucidate if high levels of Myricetin, which could be attained even with moderate wine consumption, could synergize with endogenous estrogens in the female reproductive tract, interfering with the physiological sperm fertilization process.

Human sperm anatomy: different expression and localization of phosphatidylinositol 3-kinase in normal and varicocele human spermatozoa.

Abstract Recent reports support the possible role of PI3K in sperm capacitation and acrosome reaction, although studies regarding PI3K identity in human sperm, under certain disease states such as varicocele, are still lacking. The authors, therefore, examined the expression profile and ultrastructural localization of PI3K in human semen samples, comparing healthy donors and patients with varicocele. The results obtained performing western blotting assay showed decreased PI3K expression in varicocele with respect to the "healthy" sperm. Immunogold labeling revealed human sperm cellular compartments containing PI3K, evidencing it in the head at both the membrane and nucleus and the entire tail, from the middle to the end piece of normal sperm. In varicocele PI3K label was confined to the head, with a strong reduction of specific reaction in the neck, middle piece, and tail. In conclusion, the data suggest that PI3K may play a role in the maintenance of male factor infertility associated with varicocele, and it may be further exploited as an additional molecular marker for the diagnosis of male infertility disorders.

The Omega-3 Docosahexaenoyl Ethanolamide Reduces CCL5 Secretion in Triple Negative Breast Cancer Cells Affecting Tumor Progression and Macrophage Recruitment.

Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype lacking effective targeted therapies, is considered to feature a unique cellular microenvironment with high infiltration of tumor-associated macrophages (TAM), which contribute to worsening breast cancer patient outcomes. Previous studies have shown the antitumoral actions of the dietary omega-3 docosahexaenoic acid (DHA) in both tumor epithelial and stromal components of the breast cancer microenvironment. Particularly in breast cancer cells, DHA can be converted into its conjugate with ethanolamine, DHEA, leading to a more effective anti-oncogenic activity of the parent compound in estrogen receptor-positive breast cancer cells. Here, we investigated the ability of DHEA to attenuate the malignant phenotype of MDA-MB-231 and MDA-MB-436 TNBC cell lines, which in turn influenced TAM behaviors. Our findings revealed that DHEA reduced the viability of TNBC cells in a concentration-dependent manner and compromised cell migration and invasion. Interestingly, DHEA inhibited oxygen consumption and extracellular acidification rates, reducing respiration and the glycolytic reserve in both cell lines. In a co-culture system, TNBC cells exposed to DHEA suppressed recruitment of human THP-1 cells, reduced their viability, and the expression of genes associated with TAM phenotype. Interestingly, we unraveled that the effects of DHEA in TNCB cells were mediated by reduced C-C motif chemokine ligand 5 (CCL5) expression and secretion affecting macrophage recruitment. Overall, our data, shedding new light on the antitumoral effects of DHA ethanolamine-conjugated, address this compound as a promising option in the treatment of TNBC patients.

Peptides Targeting HER2-Positive Breast Cancer Cells and Applications in Tumor Imaging and Delivery of Chemotherapeutics.

Breast cancer represents the most common cancer type and one of the major leading causes of death in the female worldwide population. Overexpression of HER2, a transmembrane glycoprotein related to the epidermal growth factor receptor, results in a biologically and clinically aggressive breast cancer subtype. It is also the primary driver for tumor detection and progression and, in addition to being an important prognostic factor in women diagnosed with breast cancer, HER2 is a widely known therapeutic target for drug development. The aim of this review is to provide an updated overview of the main approaches for the diagnosis and treatment of HER2-positive breast cancer proposed in the literature over the past decade. We focused on the different targeting strategies involving antibodies and peptides that have been explored with their relative outcomes and current limitations that need to be improved. The review also encompasses a discussion on targeted peptides acting as probes for molecular imaging. By using different types of HER2-targeting strategies, nanotechnology promises to overcome some of the current clinical challenges by developing novel HER2-guided nanosystems suitable as powerful tools in breast cancer imaging, targeting, and therapy.

Serum from Adolescents with High Polyphenol Intake Exhibits Improved Lipid Profile and Prevents Lipid Accumulation in HepG2 Human Liver Cells.

The traditional Mediterranean diet (MD) is characterized by a high phenolic-rich food intake, including in particular vegetables and fruits, but also legumes, whole grain cereals, nuts, and extra virgin olive oil. Evidence for beneficial effects of polyphenols in humans depends on the amount consumed and on their bioavailability. Here, we evaluated the association between the estimated polyphenol intake by fruits and vegetables food source and serum biochemical parameters in healthy adolescents, recruited into the DIMENU research project. Categorizing adolescents into three groups according to their estimated total polyphenol intake, we found that adolescents who declared high consumption of polyphenols had a higher adherence to the MD and had a better serum lipid profile than adolescents consuming low amounts of polyphenols. Moreover, using human HepG2 liver cells treated with oleic acid as an in vitro model for studying lipid accumulation, we showed that intracellular lipid accumulation is alleviated by serum from adolescents consuming a polyphenol-rich diet following MD recommendations. Our data underline the importance of promoting adherence to the typical MD foods as a superior strategy to prevent metabolic and chronic diseases and to ensure a better quality of life among adolescents.

FoxO3a Drives the Metabolic Reprogramming in Tamoxifen-Resistant Breast Cancer Cells Restoring Tamoxifen Sensitivity.

Tamoxifen-resistant breast cancer cells (TamR-BCCs) are characterized by an enhanced metabolic phenotype compared to tamoxifen-sensitive cells. FoxO3a is an important modulator of cell metabolism, and its deregulation has been involved in the acquisition of tamoxifen resistance. Therefore, tetracycline-inducible FoxO3a was overexpressed in TamR-BCCs (TamR/TetOn-AAA), which, together with their control cell line (TamR/TetOn-V), were subjected to seahorse metabolic assays and proteomic analysis. FoxO3a was able to counteract the increased oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) observed in TamR by reducing their energetic activity and glycolytic rate. FoxO3a caused glucose accumulation, very likely by reducing LDH activity and mitigated TamR biosynthetic needs by reducing G6PDH activity and hindering NADPH production via the pentose phosphate pathway (PPP). Proteomic analysis revealed a FoxO3a-dependent marked decrease in the expression of LDH as well as of several enzymes involved in carbohydrate metabolism (e.g., Aldolase A, LDHA and phosphofructokinase) and the analysis of cBioPortal datasets of BC patients evidenced a significant inverse correlation of these proteins and FoxO3a. Interestingly, FoxO3a also increased mitochondrial biogenesis despite reducing mitochondrial functionality by triggering ROS production. Based on these findings, FoxO3a inducing/activating drugs could represent promising tools to be exploited in the management of patients who are refractory to antiestrogen therapy.

Inhibition of cyclin D1 expression by androgen receptor in breast cancer cells--identification of a novel androgen response element.

Cyclin D1 gene (CCND1) is a critical mitogen-regulated cell-cycle control element whose transcriptional modulation plays a crucial role in breast cancer growth and progression. Here we demonstrate that the non-aromatizable androgen 5-α-dihydrotestosterone (DHT) inhibits endogenous cyclin D1 expression, as evidenced by reduction of cyclin D1 mRNA and protein levels, and decrease of CCND1-promoter activity, in MCF-7 cells. The DHT-dependent inhibition of CCND1 gene activity requires the involvement and the integrity of the androgen receptor (AR) DNA-binding domain. Site directed mutagenesis, DNA affinity precipitation assay, electrophoretic mobility shift assay and chromatin immunoprecipitation analyses indicate that this inhibitory effect is ligand dependent and it is mediated by direct binding of AR to an androgen response element (CCND1-ARE) located at -570 to -556-bp upstream of the transcription start site, in the cyclin D1 proximal promoter. Moreover, AR-mediated repression of the CCND1 involves the recruitment of the atypical orphan nuclear receptor DAX1 as a component of a multiprotein repressor complex also embracing the participation of Histone Deacetylase 1. In conclusion, identification of the CCND1-ARE allows defining cyclin D1 as a specific androgen target gene in breast and might contribute to explain the molecular basis of the inhibitory role of androgens on breast cancer cells proliferation.

From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

FoxO3a Inhibits Tamoxifen-Resistant Breast Cancer Progression by Inducing Integrin α5 Expression.

Resistance to endocrine therapy is still a major clinical challenge in the management of estrogen receptor α-positive (ERα+) breast cancer (BC). Here, the role of the Forkhead box class O (FoxO)3a transcription factor in tumor progression has been evaluated in tamoxifen-resistant BC cells (TamR), expressing lower levels of FoxO3a compared to sensitive ones. FoxO3a re-expression reduces TamR motility (wound-healing and transmigration assays) and invasiveness (matrigel transwell invasion assays) through the mRNA (qRT-PCR) and protein (Western blot) induction of the integrin α5 subunit of the α5ß1 fibronectin receptor, a well-known membrane heterodimer controlling cell adhesion and signaling. The induction occurs through FoxO3a binding to a specific Forkhead responsive core sequence located on the integrin α5 promoter (cloning, luciferase, and ChIP assays). Moreover, FoxO3a failed to inhibit migration and invasion in integrin α5 silenced (siRNA) cells, demonstrating integrin α5 involvement in both processes. Finally, using large-scale gene expression data sets, a strong positive correlation between FoxO3a and integrin α5 in ERα+, but not in ER-negative (ERα-), BC patients emerged. Altogether, our data show how the oncosuppressor FoxO3a, by increasing the expression of its novel transcriptional target integrin α5, reverts the phenotype of endocrine-resistant BC toward a lower aggressiveness.