Abstract Background: Metastatic castration-resistant prostate cancer (mCRPC) is a heterogeneous disease and often comprise molecularly distinct subtypes that differ in prognosis and therapeutic response. Super-Enhancers (SEs) are large enhancer clusters that robustly drive expression of genes controlling developmental processes and cell identity. In this study, we developed an epigenetic-based framework to determine whether mCRPC harbors subtype-specific SE programs that may reactivate distinct developmental transcriptional programs and define molecularly subtypes of disease progression. Methods: We developed a computational workflow, Super-Enhancer Analysis for Lineages (SEAL), to map SE landscapes, classify tumor subtypes and identify subtype-specific SE-driven genes. Using ROSE analysis on H3K27ac ChIP-seq data from the LuCaP and MURAL PDX mCRPC series, we constructed an integrated SE atlas. Molecular subtypes were defined through consensus clustering of SE regions and further characterized by genomic, transcriptional, and clinical features. We integrated matched RNA sequencing data to identify top-ranked SE-driven transcription factors, which were further evaluated via loss- and gain-of-function studies as well as ChIP-seq and RNA-seq analyses to define their cistromes, transcriptomes, and interacting networks. Results: We identified five distinct SE programs in mCRPC: three AR-positive subtypes (AR-1, AR-2, AR-3) and two AR-independent subtypes (NEPC-like and DNPC-like). Among the three AR-driven subtypes, AR-1 and AR-2 displayed aggressive tumor features, enriched for cell cycle, EMT, and hypoxia pathways. Each subtype exhibited a distinct SE-driven transcriptional program. Notably, we identified TWIST1, HNF1A, and TBX10 as key SE-driven transcription factors in AR-1, AR-2, and AR-3 subtypes, respectively. Among these, HNF1A, a critical transcription factor involved in hepatic development and metabolic regulation, was exclusively expressed in the AR-2 subtype. HNF1A silencing significantly reduced proliferation in vitro and in vivo and markedly suppressed glycolytic activity. AR-2 tumors produced high levels of secreted albumin, a well-established HNF1A hepatic target, which was decreased upon HNF1A silencing. ChIP-seq and RNA-seq analyses revealed that HOXB13 co-occupied HNF1A-mediated enhancers and cooperatively regulated the hepatic transcriptional programs. Conversely, HNF1A overexpression in AR-3 cells induced the expression of hepatic markers, enhanced proliferation and migration, and recapitulated features of the AR-2 subtype, indicating that HNF1A acts as a driver of hepatic lineage reprogramming. Conclusions: Our study reveals a novel HOXB13-HNF1A transcriptional axis that governs a previously undefined hepatic reprogramming in a subset of AR-driven mCRPC tumors. These findings establish a SE-based molecular classification of mCRPC and highlight HNF1A as a key regulator of metabolic and lineage programs, with potential implications for precision therapy and biomarker development in advanced prostate cancer. Citation Format: Mingyu Liu, Songqi Zhang, Nolan D. Patten, Jared G. Lourie, Xiaolin Zi, Kai Zou, Shuai Gao, Kourosh Zarringhalam, Changmeng Cai. Super-enhancer landscape analysis reveals a HOXB13-HNF1A transcriptional axis driving hepatic reprogramming in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr PR015.

Abstract Prostate cancer is one of the most frequent malignancies in males, and its course and treatment response can vary greatly. Statins, widely used cholesterol-lowering medications that target the HMG-CoA reductase gene (HMGCR), have been investigated for their potential role in prostate cancer development and progression. Statin resistance in prostate cancer may entail a variety of biochemical processes, such as changes in lipid metabolism, which allow cancer cells to persist despite statin therapy. This study examines the impact of non-statin HMGCR inhibitors (plant-derived compounds) on biopsies of metastatic castration-resistant prostate cancer (mCRPC) and mHSPC. We performed RNA sequencing data between control and non-statin HMGCR inhibitor treatment groups in PC3 (statin-sensitive, androgen-receptor negative prostate cancer cell line), DU145 (statin-resistant, androgen-receptor negative prostate cancer cell line) and LNCaP (androgen-receptor positive prostate cancer cell line). Then, The samples of mCRPC and mHSPC in Hong Kong taken during the biopsy was cultured in Aggrewell 400 to form 3D organoid. Then, we treated the organoid has statin medications and non-statin HMGCR inhibitor with futher functional and cellular phenotypes. The results of RNA-sequencing data revealed the significantly down regulation of HMGCR in DU145 cell line after treated with non-statin HMGCR inhibitor while showed no significant effect in PC3 and LNCaP. In patient-derived organoids, we found that mCRPC organoid with high level of HMGCR after statin medications has lower HMGCR after treated with non-statin HMGCR inhibitor. HMGCR level in statins-sensitive mCRPC and mHSPC samples were not significantly downregulated after non-statin HMGCR inhibitor treatment. The knock-down and overexpression of HMGCR mCRPC organoid with high level of HMGCR showed that HMGCR is target of non-statin HMGCR inhibitor in MTT assay and the total cholesterol after non-statin HMGCR inhibitor is lower after treatment (p < 0.05). Moreover, mCRPC organoid with high level of HMGCR form less 3D aggregation after non-statin HMGCR inhibitor treatment. Thus, we confirmed that our non-statin HMGCR inhibitor reduces tumor metastasis and 3D spheroid formation in statin-resistant mCRPC. This case illustrates the importance of integrating novel agents early in treatment showing high response of mCRPC to non-statin inhibitor with lower metastatic ability. This revealed high clinical impact and further translational insight to mHSPC with statin resistant signature as well. Citation Format: Salida Ali, Yao CHI, Rong NA. Innovative targeted therapy for metastatic prostate cancer using non-statin HMGCR inhibitor: insights from patient-derived organoids and clinical data in Hong Kong [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Prostate Cancer Research and Treatment; 2026 Jan 20-22; Philadelphia PA. Philadelphia (PA): AACR; Cancer Res 2026;86(2_Suppl):Abstract nr B002.

Cancer represents a major global health challenge, with steadily increasing incidence rates worldwide. A hallmark of cancer development is metabolic reprogramming, whereby cancer cells alter their metabolic behavior to meet the demands of energy production, biosynthesis, and redox homeostasis, distinguishing them from normal cells. Numerous environmental, behavioral, and biological factors contribute to cancer risk, including alcohol consumption, tobacco use, frequent intake of fast foods, exposure to environmental pollutants, viral infections such as human immunodeficiency virus (HIV), psychological stress, and dysregulation of key metabolic pathways involving glucose, amino acids, and fatty acids. Cancer progression involves the transformation of normal cells into highly malignant and invasive tumors, often accompanied by genomic instability. Emerging evidence suggests that modifiable lifestyle factors play a crucial role in both the development and prevention of cancer. Adoption of healthy dietary patterns, calorie restriction, regular physical activity, cessation of smoking and alcohol use, and avoidance of obesity-promoting behaviors such as excessive consumption of fatty foods and hot beverages can help regulate metabolic alterations and significantly reduce cancer risk. This review highlights the interplay between risk factors, metabolic changes, and lifestyle interventions in cancer development and prevention.

The hypoxic microenvironment within breast cancer tumors leads to the sustained activation of hypoxia-inducible factors (HIFs), notably HIF-1α, which, in turn, triggers adaptive responses such as angiogenesis and metabolic reprogramming. These processes contribute to tumor invasion, progression, metastasis, and therapy resistance. Although a substantial portion of the human genome is transcribed into non-coding RNAs (ncRNAs), which have been shown to play key regulatory roles in the development and progression of breast cancer, the interplay between HIFs and ncRNAs—and how such crosstalk influences breast cancer pathogenesis—remains poorly understood. This review aims to systematically outline the mechanisms of hypoxia-related signaling and ncRNA function in breast cancer, with a focus on their molecular interactions in disease progression and their potential clinical implications.

Background and Objectives: Aggressive cancer development is characterized by rapid tumor growth and progressive immune dysfunction. Tumor-derived microRNAs (miRNAs) emerge as master regulators of both malignant transformation and immune evasion, making them promising therapeutic targets. Using the highly aggressive CT-26 peritoneal adenomatosis model, this study explored the potential of selective miRNA inhibition to simultaneously suppress tumor growth and overcome immunosuppression. Methods and Results: Our results revealed that inhibition of miR-155, miR-21, and miR-17 by methylsulfonyl phosphoramidate (mesyl) oligonucleotides exhibited markedly different therapeutic profiles. miR-155 inhibition demonstrated minimal efficacy. miR-21 suppression provided early tumor regression and prevented cancer-associated thymic atrophy, translating into extended survival. miR-17 inhibition displayed delayed but superior tumor growth inhibition, significantly reducing pathologically elevated polymorphonuclear myeloid-derived suppressor cell (MDSC) populations, and nearly doubled animal lifespan. Combination therapy targeting all three miRNAs integrated these complementary mechanisms, maintaining consistent anti-tumor efficacy across early and late stages while providing thymic protection and MDSC reduction. Importantly, therapeutic responses in vivo substantially exceeded predictions based on in vitro tumor cell proliferation and motility measurements, revealing critical contributions of systemic immunomodulation. Conclusions: These findings demonstrate that miRNA inhibition reshapes tumor–immune interactions, positioning anti-miRNA therapeutics as immunomodulatory agents for effective colorectal cancer treatment.

Enzymes from the cytochrome P450 (CYP) superfamily, especially from families CYP1, CYP2, and CYP3, play a decisive role in phase I of drug and xenobiotic metabolism in mammalian organisms. The enzymes are responsible for metabolic conversion and detoxification of a plethora of foreign molecules. Metabolic conversion of pro-carcinogenic compounds links CYP enzyme activities to cancer development, while in addition oncogenic pathways have been shown to regulate the expression of CYP genes, together with the well-known regulation by nuclear receptors acting as ligand-activated transcription factors triggered by exposure to xenobiotics. Specifically, the Wnt/β-catenin signaling pathway is among the recently established transcriptional regulators of CYP enzymes. β-Catenin is well-known as a key player in organism development and, when aberrantly activated, a major oncogenic driver of carcinogenesis. While the latter phenomena are rather well-described, new evidence suggests that CYP enzymes themselves may, under certain conditions, also affect the activity of the β-catenin pathway and thereby could impact on carcinogenesis in a way different from toxifying or detoxifying foreign compounds. This review focuses on the currently available knowledge about the regulation of β-catenin-dependent signaling by CYP enzymes. The synopsis of data reveals the possibility of a previously undervalued role of CYPs in the regulation of Wnt/β-catenin signaling, and possible molecular mechanisms are highlighted.

Somatic mutations, key alterations in cancer development, exert differential effects across tissues and biological layers, such as transcriptomes, proteomes, and post-translational modifications (PTMs). Although previous pan-cancer studies have characterized the molecular landscape of cancer, the effects of individual somatic mutations across different tissues remain insufficiently explored. Here, we developed Panorama to evaluate the oncogenic potential of single somatic mutations across all cancer types. We collected cancer proteogenomics or multiomics data from over 10 000 individuals across 19 cancer types. Based on five evaluation criteria, we assessed whether a specific mutation affects the abundance of a particular gene’s transcriptome, proteome, or phosphoproteome; the tumor microenvironment; specific RNA- or protein-based signaling pathways; and outlier-level overexpression of PTMs, aiding in potential drug target identification. By leveraging five oncogenic metrics, Panorama quantifies the oncogenic potential of individual somatic mutations and provides a framework for identifying driver mutations by incorporating their downstream effects. With Panorama, researchers can integrate cancer proteogenomics data, providing a comprehensive approach that enhances our understanding of single somatic mutations in specific tissues. Finally, Panorama was developed as a web-based database to ensure easy access for researchers and is freely available at http://139.150.65.64:8080/or https://github.com/prosium/panorama.

Early prevention of pathological changes underlying gastric cancer (GC) development is a critical strategy, offering the most effective opportunity to limit malignant progression and improve patient outcomes. We have previously demonstrated that Helicobacter pylori (Hp) (cagA+vacA+) contributes to GC development by activating gastric fibroblasts toward CAF-like phenotype, eliciting aggressive, cancer stem cells (CSCs)-related malignant transformation of LGR5+ normal epithelial cells. A key mediator of these processes appears to be the NF-κB/STAT3 axis. Therefore, our aim was to investigate the protective role of hydrogen sulfide (H2S) as a potential novel strategy for counteracting Hp-induced fibroblast reprogramming. Human fibroblasts were infected with Hp (cagA+vacA+) for 120 h. The fast-releasing H2S donor NaHS (50, 100, 200 and 400 µM) was added every 24 h. Activation markers, corresponding signaling pathways, H2S release and activities of H2S-metabolizing enzymes were determined. NaHS reduced Hp-induced fibroblast activation and their pro-inflammatory, pro-tumorigenic markers, which was associated with the inhibition of NF-κB/STAT3 axis and Twist expression. Additionally, it modulated sulfur metabolism while preserving sulfur-enzyme homeostasis. NaHS limited Hp adhesion (high doses), reduced reinfection-induced activation and increased sensitivity of Hp to metronidazole. These findings suggest that H2S signaling may represent a modulatory factor of NF-κB/STAT3-driven inflammatory responses during Hp infection and warrant further investigation.

In the years following pregnancy, breast cancer risk is elevated, particularly for hormone receptor negative (HR-) tumors. Exposure to high maternal circulating estrogens, when the breast is vastly remodeling in structure and morphology, has been associated with HR- tumor risk. Estrogen metabolite profiles in nonpregnant women, notably the ratio of 2:16 hydroxylation (OH) pathway metabolites, are associated with postmenopausal breast cancer development; whether estrogen metabolism during pregnancy influences subsequent HR- breast cancer risk is unknown. We conducted a population-based case-control study in women 19-39years identified in the Finnish Maternity Cohort Biobank and linked with the Finnish Cancer Registry to identify breast cancer diagnoses within 20years of pregnancy. Estrogens and metabolites were measured using highly reliable and sensitive LC-MS/MS methods in serum collected during the first and second trimesters of pregnancy. Included were invasive, ER-/PR- breast cancer cases (n = 449) and controls (n = 449) matched on maternal age at index pregnancy, parity, calendar year of serum collection, gestational week of blood collection, and number of sample freeze/thaw cycles. Associations between the estrogens and breast cancer risk were estimated using odds ratios (ORs) with 95% confidence intervals (CIs) from conditional logistic regression models. The median years of follow-up between blood collection and breast cancer diagnosis/control selection was 9 (range 0-19). Ninety-three percent of cases were < 50years of age at breast cancer diagnosis. Total estrogens were positively associated with ER-/PR- breast cancer (OR associated with a doubling of total estrogens 1.16; 95% CI 1.02-1.32), as were metabolites in the 16-pathway including estriol [OR 1.11; 95% CI 1.01-1.22], 16-epiestriol [OR 1.11; 95% CI 1.01-1.21)], 17-epiestriol [OR 1.06; 95% CI 1.01-1.13], and total 16-hydroxylation pathway metabolites [OR 1.11; 95% CI 1.00-1.24]. There was no clear association with the ratio of 2:16 hydroxylation pathway metabolites. Some associations differed by parity, age at diagnosis, and gestational timing of blood collection, but interactions were not statistically significant. Results were similar when restricted to cases occurring within 15years since pregnancy. This prospective study demonstrated positive associations of estrogen metabolites in pregnancy and risk of mostly premenopausal ER-/PR- breast cancer, but the magnitudes varied by metabolite. No strong or consistent pattern for one metabolic pathway emerged suggesting that total estrogen concentrations during pregnancy are associated with subsequent HR- breast cancer development, regardless of how they are metabolized.

Glucagon-like peptide-1 (GLP-1) medicines reduce food intake, body weight, insulin resistance and inflammation, thus improving outcomes for people with type 2 diabetes and obesity and potentially contributing to decreased cancer incidence. GLP-1 medicines acting through weight loss-dependent and weight loss-independent mechanisms hold potential for suppression of tumorigenesis and reduction of rates of obesity-associated cancer. In this Perspective, we summarize data on cancer incidence from trials and registries in individuals with type 2 diabetes, describe the actions of GLP-1 medicines on preclinical cancer models and highlight possible direct and indirect mechanisms linking GLP-1R signaling to cancer development and progression.

As the first bacterium to be deemed a class I carcinogen by the World Health Organization in 1994, Helicobacter pylori has paved the way for studying complex host-pathogen interactions. While 1982 marked the discovery of this helical-shaped microorganism found in gastric biopsies by Drs. Robin Warren and Barry Marshall, it took years to link H. pylori infection to gastric inflammation, ulcers, and adenocarcinoma (recognized by a Nobel Prize in 2005). Further investigations into how H. pylori colonizes the stomach, the identification of key virulence factors (such as VacA, CagA, and outer membrane proteins), and global epidemiological studies solidified the impact of H. pylori on gastric disease. This review details the seminal discovery of H. pylori and subsequent work that cemented its status as a microbial carcinogen. Because chronic H. pylori infection and progressive changes to the tissue environment prior to cancer development can span years/decades, studying H. pylori pathogenesis has been challenging. We focus on the importance of using animal models, in particular mouse models, to recapitulate hallmarks of H. pylori-driven human disease. Finally, we highlight recent findings illustrating how H. pylori has adapted to survive and utilize oxidative stress induced during infection, which potentiates cancer development. Due to the long-lasting nature of H. pylori infection and associated remodeling of the host environment that, in turn, promotes carcinogenesis, H. pylori stands as a model organism for understanding other chronic bacterial infections in humans and pathogen-associated malignancies.

The tumor microenvironment (TME) plays a central role in cancer progression and metastasis. A key feature of the TME is extracellular acidity, which promotes disease progression, immune evasion, and drug resistance. Tumor acidity is increasingly recognized as a critical factor in cancer development and a negative prognostic indicator. Here, we demonstrate that the membrane glycoprotein dysadherin promotes colorectal cancer (CRC) malignancy by modulating TME acidity. Comprehensive bioinformatics and pathological analyses of CRC patient samples revealed that increased tumor acidity is a hallmark of CRC progression and strongly correlates with high expression of dysadherin. Functional studies confirmed that dysadherin enhances malignant traits, particularly under acidic conditions. Mechanistically, dysadherin activates the integrin/FAK/STAT3 signaling pathway, leading to the upregulation of carbonic anhydrase 9 (CA9). CA9 facilitates proton export, contributing to extracellular acidification while maintaining intracellular pH homeostasis, thereby enabling cancer cells to survive and thrive in acidic environments. In a murine liver metastasis model, dysadherin deletion impaired cellular adaptation to the acidic TME and markedly attenuated metastatic colonization, whereas restoring CA9 expression effectively rescued metastatic potential. Overall, our findings identify the dysadherin/CA9 axis as a potential therapeutic target in CRC and provide new insights into how tumors exploit acidosis to drive malignant development and progression.

Bidirectional effect of intestinal microbiome and host in circadian rhythm disruption: Environmental factors and breast cancer development.

Structure-based design and synthesis of novel highly potent and selective KRASG12C inhibitors.

Epithelia maintain their barrier function through the proliferative and plastic behavior of stem cells that drive continuous tissue regeneration. However, these same properties render epithelia susceptible to tumorigenesis. The skin, the largest epithelial barrier, is the source of the most prevalent human cancers, yet the molecular mechanisms by which stem cells and their microenvironment cooperate to promote cutaneous cancer development remain incompletely defined. Prior work demonstrated that genotoxic injury in normal skin activates epithelial-dermal inflammasome signaling that drives epithelial stem cell hyperproliferation and misspecification. Here, we investigated whether this mechanism also operates in diseased skin. We found that stem cell misspecification is a broadly conserved feature across pathological skin conditions but is absent in normally proliferating tissue. Notably, inflammasome activation is detected in both epithelial and dermal compartments of cutaneous squamous cell carcinoma (cSCC), but not in other skin pathologies. Mechanistically, oncogenic KRAS expression in keratinocytes triggers inflammasome activation prior to tumor formation non-cell autonomously. Furthermore, IL-1 signaling is activated in fibroblasts adjacent to the cSCC tumor interface, but not in the overlying epithelium. Taken together, these findings support a model in which KRAS-driven epithelial-fibroblast inflammasome crosstalk establishes a feed-forward IL-1 signaling loop that enhances the tumor-promoting microenvironment in cSCC.

Cell morphology and its mechanical properties are crucial factors in cancer development, affecting migration, invasiveness, and the potential risk of metastasis. However, most studies address these aspects separately, limiting the understanding of how morphological complexity relates to cellular mechanics. This work presents an integrated approach that simultaneously quantifies morphology and viscoelasticity in the human osteosarcoma cell line MG-63. Stress–relaxation experiments and optical imaging of the same cells were performed using a custom-built system that couples Atomic Force Microscopy (AFM) with an inverted optical microscope. Morphometric parameters were extracted from cell contours, while viscoelastic properties were obtained by fitting AFM data to the Fractional Kelvin (FK) and Fractional Zener (FZ) models. Among the morphological descriptors, the Shape Complexity (SC) was proposed. It is derived from the Lobe Contribution Elliptical Fourier Analysis (LOCO-EFA), which captures fine-scale contour features overlooked by conventional metrics. Experimental results show that, in MG-63 cells, higher SC values are associated with greater stiffness, indicating a correlation between cell shape complexity and cell stiffness. Furthermore, loading-rate analysis shows that the FZ model captures strain-rate-dependent stiffening more effectively than the FK model. This methodology provides a first approach to jointly analyzing quantitative morphological parameters and mechanical properties, underlining the importance of combined studies to achieve a comprehensive understanding of cell behavior.

Background: Mutations in the KRAS gene play a pivotal role in lung cancer development and progression and are becoming increasingly important in therapeutic decision-making. The detection of these mutations in circulating tumor DNA (ctDNA) has attracted attention as a minimally invasive diagnostic approach. However, the accuracy reported in different studies varies widely. Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA-DTA guidelines. Eligible studies evaluated the detection of KRAS mutations in ctDNA in plasma or serum for lung cancer diagnosis and reported sufficient data to construct 2 × 2 contingency tables. Primary pooled estimates of sensitivity, specificity and likelihood ratios were calculated using aggregated 2 × 2 contingency tables. Additionally, a bivariate random-effects model was applied in a secondary analysis to investigate between-study heterogeneity. Results: Nine diagnostic study arms comprising 691 patients met the inclusion criteria. Across all datasets, there were 255 true positives, 19 false positives, 136 false negatives, and 281 true negatives. The pooled sensitivity was 65.2%, while the pooled specificity was 93.7%. The positive likelihood ratio was 10.35, and the negative likelihood ratio was 0.37, resulting in a diagnostic odds ratio of 28.0, which indicates strong rule-in capability. Sensitivity showed moderate heterogeneity across studies. In contrast, specificity demonstrated minimal heterogeneity. Conclusions: ctDNA-based detection of KRAS mutations demonstrates high specificity but moderate sensitivity for diagnosing lung cancer. These findings suggest that a KRAS liquid biopsy could be a valuable complementary diagnostic tool, particularly when a tissue biopsy is not possible or is inadequate, and it could support more personalized decision-making as analytical technologies continue to advance.

Breast cancer is genetically and histologically heterogenous, and is influenced by a variety of factors, including the tumor microenvironment (TME). The PAM50 subtypes; Luminal A, Luminal B, Normal-like, Basal-like and Her2-enriched, are associated with different tumor phenotypes and overall survival. The quantity and quality of immune cell infiltration in breast tumors play a key role in cancer development and progression and are associated with survival and treatment response. We used multiplex immunohistochemistry, single-cell RNA sequencing, and two deconvolution algorithms to explore the immune landscape across PAM50 subtypes. Immunostaining of CD3+ T cells, tryptase+ mast cells, CD20+ B cells, CD68+ CD163+ macrophages, and CD66b+ granulocytes revealed marked differences in tumor immune infiltrates according to breast cancer subtypes. Luminal tumors were relatively deprived of T cells and B cells, while exhibiting sparse to moderate amounts of macrophage infiltration. In contrast, Her2-enriched tumors exhibited a moderate immune presence, with sparse to moderate T cell infiltration and moderate infiltration of B cells and macrophages. At the other end of the spectrum, Basal-like tumors stood out for their strikingly rich immune environment and are heavily infiltrated by T cells, B cells, and macrophages. The results from the single-cell and deconvolution analyses confirmed subtype-specific immune microenvironments, which also allowed us to observe increased levels of natural killer (NK) and CD8+ T cells in Her2-enriched and Basal-like subtypes. In conclusion, our findings demonstrate significant differences in the immune tumor microenvironment between the established breast cancer molecular subtypes.

Background/Objective: Prostate cancer (PCa) is the leading cause of death in the ageing male population across the globe, and trace metals have garnered much attention due to their sometimes-dual role in cellular mechanisms, as such contribute to the development and progression of prostate cancer. Methods: This review consolidates the results of case-control studies that investigated the concentrations of certain trace metals—Arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn), nickel (Ni), lead (Pb), selenium (Se), and zinc (Zn) in various biological samples. Results: There are decreased concentrations of Se and Zn and increased Cd concentrations in samples of PCa patients when compared to healthy controls. As, Hg, Ni, and Pb concentrations have proven to be insignificant. Conclusions: There are other variables to consider and limitations that need to be investigated in studies of this nature; however, the results have been consistent in that increased exposure to toxic metals such as Cd, along with a deficiency in protective essential nutrients like Zn and Se, tends to produce a prostatic environment.

Genus beta (β) human papillomaviruses (HPVs) potentially contribute to the development of non-melanoma skin cancer. Yet, comparatively little is known about their biology. In particular, details about initial infection, i.e., host cell entry, remain mostly elusive. During initial characterization of β HPV5 pseudovirion (PsV) preparations, surprisingly large amounts of filamentous particles were found besides the prototypical icosahedral (T = 7) virions. Whether these filamentous particles actively contribute to or interfere with infectivity of the spherical viruses is unknown. Using a combination of morphological, biochemical, and virological methods, we showed that the filamentous particles are non-infectious. Moreover, they interfered with the initial step of infection, i.e., binding to cellular heparan sulfate proteoglycans (HSPGs), and served as a decoy for soluble glycosaminoglycans, thereby modulating infectivity by enhancing infectious PsV binding. This explains previous seemingly contradictory findings on HPV5 binding to HSPGs. Importantly, in HPV5 skin warts from an immunocompromised patient, no filamentous particles were observable highlighting differences in the assembly of pseudovirions and native viruses.IMPORTANCEPapillomaviruses contribute to numerous cancer incidents and significant mortality despite available vaccinations. Hence, high-risk α HPVs have been the focus of most research in the past. However, there are indications that less well-studied β HPVs may also contribute to certain malignancies. Little is known about their mode of cell invasion, and available data appear partially contradictory. Our work demonstrated that HPV5 as a model β HPVs yielded high amounts of non-infectious filamentous particles during PsV production. These acted as modulators of infection by the infectious spherical particles. Removing these filamentous particles showed that HPV5 engaged HSPGs as the primary receptor for cell binding, similar to high-risk α HPV, indicating a conserved feature not only among α, but also among β HPVs, thereby explaining previous contradictions.