Hormone-dependent Cancer Research Articles

The correlation between the expression of androgen receptor splice variant-7 (AR-V7) protein with the time of occurrence of castration-resistant prostate cancer and overall survival in prostate cancer in Indonesian population

Abstract Introduction Prostate cancer follows a natural trajectory characterized by genetic alterations that transform initially hormone-sensitive cancer cells into castration-resistant prostate cancer (CRPC), which is associated with high mortality. This study endeavours to elucidate the predictive role of androgen receptor splice variant 7 (AR-V7) protein expression in determining the time to CRPC onset and overall survival in prostate cancer patients. Methods This retrospective cohort study utilized paraffin-embedded tissue block samples collected from prostate cancer patients undergoing Androgen Deprivation Therapy at Dr. Sardjito General Hospital between 2016 and 2022 (n = 47). AR-V7 protein expression was assessed via immunohistochemistry. Time to CRPC and overall survival were subjected to Log- Rank analysis and Cox regression. Results Patients exhibiting AR-V7 + protein expression experienced a considerably shorter time to CRPC onset compared to those with AR-V7-expression (21.13 vs. 40.05 months; p-value = 0.020). In the assessment of overall survival, patients with AR-V7 + protein expression demonstrated significantly poorer overall survival rates in contrast to those with AR-V7-expression (17.00 vs. 22.00 months; p = 0.00). Conclusions Diminished AR-V7 + protein expression emerges as a predictive indicator for a shortened time to CRPC onset. Moreover, AR-V7 protein expression holds prognostic value in predicting overall survival among prostate cancer patients.

Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance.

RAF protein kinases are major RAS effectors that function by phosphorylating MEK. Although all three RAF isoforms share a conserved RAS binding domain and bind to GTP-loaded RAS, only ARAF uniquely enhances RAS activity. Here we uncovered the molecular basis of ARAF in regulating RAS activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF-RAS condensates tethered to the plasma membrane. These structures concentrate active RAS locally, impeding NF1-mediated negative regulation of RAS, thereby fostering receptor tyrosine kinase (RTK)-triggered RAS activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF-RAS protein condensates as distinct subcellular structures sustaining RAS activity and facilitating oncogenic RAS signaling. Targeting ARAF-RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.

Advances in understanding the role of squalene epoxidase in cancer prognosis and resistance.

Recently, there has been burgeoning interest in the involvement of cholesterol metabolism in cancer. Squalene epoxidase (SQLE), as a critical rate-limiting enzyme in the cholesterol synthesis pathway, has garnered attention due to its overexpression in various cancer types, thereby significantly impacting tumor prognosis and resistance mechanisms. Firstly, SQLE contributes to unfavorable prognosis through diverse mechanisms, encompassing modulation of the PI3K/AKT signaling pathway, manipulation of the cancer microenvironment, and participation in ferroptosis. Secondly, directing efforts towards targeting SQLE, via mechanisms such as the PI3K/AKT pathway, presents promising avenues for overcoming resistance to conventional therapies such as endocrine cancer therapy, chemotherapy, immunotherapy, or radiotherapy. Moreover, the effectiveness of SQLE protein inhibitors in impeding cancer progression may either depend directly on SQLE inhibition or function through alternative pathways separate from SQLE. This mini-review offers insights into the intricate mechanisms through which SQLE affects the prognosis and resistance profiles across diverse cancer types, while succinctly elucidating the mechanisms underpinning the anticancer effects of SQLE protein inhibitors. Furthermore, this mini-review underscores the necessity for further investigations into the interplay between SQLE and cancer, proposing potential avenues for future research, with the aim of serving as a reference for exploring the mechanisms governing the role of SQLE in cancer regulation.

A Pan-Cancer Analysis of Age and Sex Differences in Cancer Incidence and Survival in the United States, 2001–2020

Background: In cancer, age and sex are often studied individually, but the impact of the intersection of these factors on cancer incidence and survival remains unclear. Using population-level data, we provide an up-to-date analysis of the impact of sex and age on cancer incidence and survival. Methods: Using data from the United States Cancer Statistics public use research database and the Centers for Disease Control and Prevention’s National Program of Cancer Registries Survival database, we assessed sex and age differences in the incidence and survival of malignant cancers diagnosed from 2001 to 2020. Results: Males experienced higher cancer incidence than females in all sites and age groups, excluding 20–29- and 30–39-year-olds. The highest Male-to-female (M:F) age-adjusted incidence rates (IRR) were observed in mesothelioma within ages 80+ (IRR: 5.48; 95% CI: 5.25–5.71; p < 0.001), and lowest in endocrine cancer within ages 20–29 years (M:F IRR: 0.20; 95% CI: 0.20–0.21; p < 0.001). Among all sites and age groups, excluding 0–9 years, males experienced worse survival than females, particularly within ages 20–29 years (Hazard Ratio (HR): 2.19; 95% CI: 2.15–2.23; p < 0.001). Highest M:F HRs were observed in endocrine system cancers within ages 20–29 (HR: 3.52; 95% CI: 3.15–3.94; p < 0.001), and lowest among lymphomas within ages 0–9 (HR: 0.74; 95% CI: 0.63–0.87; p < 0.001). Conclusions: Significant age and sex differences in cancer incidence and survival were observed across the US from 2001 to 2020. Males had a higher cancer incidence compared to females, with notable exceptions for younger age groups among certain types, suggesting age may be a critical component in further understanding the biology of sex differences in cancer.

Ovarian sex cord-stromal cell tumors and the risk of sex hormone-sensitive cancers.

Sex cord-stromal cell tumors (SCST) are rare tumors of the ovary. Some of the SCSTs secrete hormone originating from the sex or stromal cell of the ovaries. Previous studies have indicated an increased risk of breast and endometrial cancers. However, these studies focused only on the SCST-subtype adult granulosa cell tumor, the estimates stem from selected cohorts and lack a well described cohort making it difficult to adjust for possible confounders. We examinined the incidence of other primary hormone sensitive cancers and comparing the risk to a matched cohort of women without SCST. This is a nested cohort study evaluating women diagnosed with sex cord-stromal cell tumors (SCSTs). We established the cohort of women diagnosed with SCSTs using Systematized Medical Nomenclature for Medicine (SNOMED) codes from the Danish Pathology Register. SCST diagnoses were considered valid if the primary diagnosis was established at a tertiary referral center or confirmed by at least two pathologists. A 1:10 matched control group, matched on birth year, was selected from national registries. Variables for follow up of cases and controls were drawn from national registries including assessment of rates of breast, ovarian and endometrial cancer, hormone use, Charlson Comorbidity Index and sociodemographics. Hazard ratios (HRs) for cancer rates were calculated using multivariate Cox proportional hazards models with SCST exposure estimated in early and delayed models to capture cancer rates over time. Standardized incidence ratios (SIRs) for very rare SCSTs were determined using log-linear Poisson models. Among the 1,516 tumors assigned SNOMED codes for SCSTs, 1,387 met the inclusion criteria after pathologic chart review. The majority had benign tumors, primarily thecoma/fibrothecoma (66%), while 26% had adult granulosa cell tumors (aGCTs). Increased rates for breast cancer were found in thecomas (HR: 1.2; 95% CI 1.0-1.4). In the analysis of all SCSTs combined, an increased rate of synchronous endometrial cancer was found (HR: 3.3; 95% CI 2.7-4.1). In sub-group analysis, malignant and benign SCSTs showed significantly higher HRs for synchronous endometrial cancer, notably in aGCTs (HR: 10.7; 95% CI 5.7-20.1). In the model assessing the rates of endometrial cancer two months after surgical removal of the SCST, no increased rates were found. Sertoli cell tumors were linked to an increased incidence of breast cancer (SIR: 18.9; 95% CI 2.7-134). Both Sertoli and Leydig cell tumors were associated with a higher incidence of synchronous endometrial cancer, with SIRs of 41.4 (95% CI 10.4-166) and 44.9 (95% CI 18.7-108), respectively. In conclusion, women with SCSTs have an increased rate of synchronous endometrial cancer and women with benign SCSTs have an increased rate of synchronous ovarian cancer. A marginally increased rate of breast cancer was found in women with thecomas. There is no increased rate of breast cancer among women with aGCT. It is recommended that women diagnosed with hormone-secreting SCSTs and additional risk factors for endometrial cancer (abnormal uterine bleeding and/or abnormal endometrial thickness) undergo an endometrial biopsy to assess for the presence of cancer.

Incidence and risk factors for insulinoma diagnosed in dogs under primary veterinary care in the UK

Insulinoma is the most common pancreatic tumor diagnosed in dogs. This study aimed to report incidence risk, breed predispositions and other demographic risk factors for insulinoma diagnosed in dogs under primary veterinary care in the UK. The VetCompass Program supports research on anonymized electronic health records (EHRs) from dogs under UK veterinary care. This study included all VetCompass EHRs from dogs under primary veterinary care during 2019. Multivariable logistic regression analysis was used to evaluate demographic risk factors for insulinoma diagnosis. Of 2,250,741 study dogs, 278 were confirmed as insulinoma cases at any date. The estimated 2019 incidence risk was 0.003% (95% CI 0.002–0.004%). Compared to crossbreeds, predisposed breeds included Dogue de Bordeaux, German Pointer, Flat Coated Retriever, Boxer and West Highland White Terrier. The Labrador Retriever showed decreased odds for insulinoma diagnosis. Additionally, being a terrier breed and being a breed predisposed to other endocrine cancers were associated with increased odds for insulinoma diagnosis. Other risk factors associated with increased odds for insulinoma diagnosis included being female neutered, being 9 - <15 years of age, having an adult median bodyweight of 20 - <30 kg and having a bodyweight above the median for the sex/breed. This is the first study to report the epidemiology of canine insulinoma in dogs under primary veterinary care, resulting in crucial leads for further research in the epidemiology and etiology of canine insulinoma and possible links of canine insulinoma with other canine endocrine cancers. Additionally, the results can aid veterinarians to identify dogs at greater risk of insulinoma.

Utilisation of the Innovative [18F]-Labelled Radiotracer [18F]-BIBD-071 Within HR+ Breast Cancer Xenograft Mouse Models.

Background/Objectives: Aromatase plays a crucial role in the conversion of androgens to oestrogens and is often overexpressed in hormone-dependent tumours, particularly breast cancer. [18F]BIBD-071, which has excellent binding affinity for aromatase and good pharmacokinetics, has potential for the diagnosis and treatment of aromatase-related diseases. The MCF-7 cell line, which is hormone receptor-positive (HR+), was used in the assessment of the novel [18F]-labelled radiotracer [18F]BIBD-071 via positron emission tomography (PET) imaging of an HR+ breast cancer xenograft model. Methods: [18F]BIBD-071 was synthesised, radiolabelled, and then subjected to in vitro stability testing. MCF-7 cells were cultured and implanted into BALB/c nude mice to establish subcutaneous tumour models. MicroPET/CT imaging was conducted after injection of the tracer at 1 and 2 h, and a blocking study was also conducted using the aromatase inhibitor letrozole. A block experiment was used to prove the specificity of the probe. Biodistribution studies were performed at 0.5, 1, and 2 h post injection (p.i.). Immunofluorescence was used to assess aromatase expression in MCF-7 cells. Results: [18F]BIBD-071 showed excellent in vitro stability and specific uptake in an MCF-7 xenograft tumour model. MicroPET/CT imaging at 1 and 2 h p.i. revealed excellent tumour visualisation with a favourable tumour-to-background ratio. Biodistribution data revealed high tracer uptake in the liver, small intestine, and stomach, with significant washout from the bloodstream and tumour over time. The tumour uptakes at 0.5 h, 1 h, and 2 h were 3.84 ± 0.13, 2.5 ± 0.17, and 2.54 ± 0.32, respectively. The tumour uptake significantly decreased between 0.5 h and 1 h (p < 0.0001), whereas there was no significant difference between 1 and 2 h. The tumour/background ratios at 0.5 h, 1 h, and 2 h were 1.19 ± 0.03, 1.12 ± 0.17, and 1.42 ± 0.11, respectively. Immunofluorescence confirmed robust aromatase expression in MCF-7 cells, which was correlated with [18F]BIBD-071 tumour uptake. Conclusions: [18F]BIBD-071 is a promising PET tracer for diagnosing and monitoring HR+ breast cancer, warranting further research into hormone-dependent cancers.

Improving neuroendocrine tumor treatments with mathematical modeling: lessons from other endocrine cancers

Neuroendocrine tumors (NETs) occur sporadically or as part of rare endocrine tumor syndromes (RETS) such as Multiple Endocrine Neoplasia 1 and Von-Hippel Landau syndromes. Due to their relative rarity and lack of model systems, NETs and RETs are difficult to study, hindering advancements in therapeutic development. Causal, or mechanistic mathematical modeling, is widely deployed in disease areas such as breast and prostate cancers, aiding understanding of observations as well as streamlining in vitro and in vivo modeling efforts. Mathematical modeling, while not yet widely utilized in NETs research, offers an opportunity to accelerate NET research and therapy development. To illustrate this, we highlight examples of how mathematical modeling associated with more common endocrine cancers has been successfully used in the preclinical, translational, and clinical settings. We also provide a scope of the limited work that has been done in NETs and map how these techniques can be utilized in NET research to address specific outstanding challenges in the field. Finally, we include practical details such as hardware and data requirements, present advantages and disadvantages of various mathematical modeling approaches, and discuss challenges of using mathematical modeling. Through a cross-disciplinary approach, we believe that many currently difficult problems can be made more tractable by applying mathematical modeling and that the field of rare diseases in endocrine oncology is well-poised to take advantage of these techniques.

Metabolic Switch in Endocrine Resistant Estrogen Receptor Positive Breast Cancer.

The development of endocrine resistance remains a significant challenge in the clinical management of estrogen receptor-positive (ER+) breast cancer. Metabolic reprogramming is a prominent component of endocrine resistance and a potential therapeutic intervention point. However, a limited understanding of which metabolic changes are conserved across the heterogeneous landscape of ER+ breast cancer or how metabolic changes factor into ER DNA binding patterns hinder our ability to target metabolic adaptation as a treatment strategy. This study uses dimethyl fumarate (DMF) to restore tamoxifen (Tam) and fulvestrant (Fulv) sensitivity in endocrine-resistant cell lines and investigates how metabolic changes influence ER DNA-binding patterns. To address the challenge of metabolic adaptation in anti-endocrine resistance, we generated Tam and Fulv resistance in six ER+ breast cancer (BC) cell lines, representing ductal (MCF7, T47D, ZR75-1, and UCD12), lobular (MDA-MB-134--VI), and HER2 amplified (BT474) BC molecular phenotypes. Metabolomic profiling, RNA sequencing, proteomics, and CUT&RUN assays were completed to characterize metabolic shifts, transcriptional and protein changes, and ER DNA-binding patterns in resistant cells. Dimethyl fumarate was assessed for its ability to reverse Tam and Fulv resistance, restore tricarboxylic acid cycle (TCA) cycle function, and restore parental cell (endocrine sensitive) ER DNA binding patterns. Tamoxifen-resistant (TamR) and fulvestrant-resistant (FulvR) cells exhibited disrupted TCA cycle activity, reduced glutathione levels, and altered nucleotide and amino acid metabolism. DMF treatment replenished TCA cycle intermediates and reversed resistance in both TamR and FulvR cells. DMF also increased mevalonate pathway enzyme expression in both TamR and FulvR cells, with TamR cells upregulating enzymes in the cholesterol synthesis phase and FulvR enhancing enzymes in the early part of the pathway. DMF restored ER DNA-binding patterns in TamR cells to resemble parental cells, re-sensitizing them to Tam. In FulvR cells, DMF reversed resistance by modulating ER-cofactor interactions but did not restore parental ER DNA-binding signatures. Our findings provide new insights into how metabolic reprogramming affects ER DNA-binding activity in endocrine-resistant breast cancer. We demonstrate how altering metabolism can reprogram ER signaling and influence resistance mechanisms by targeting metabolic vulnerabilities, such as TCA cycle disruptions. Additionally, our data provide a comprehensive metabolomic, RNA-seq, and CUT&RUN data set relevant to tumor metabolic adaptation leading to acquired endocrine resistance in highly utilized ER+ breast cancer cell lines. This study improves our understanding of how metabolic states alter ER function in endocrine-resistant breast cancer.

Alcohol Consumption and Breast and Ovarian Cancer Development: Molecular Pathways and Mechanisms.

Alcohol consumption has been consistently linked to an increased risk of several cancers, including breast and ovarian cancer. Despite substantial evidence supporting this association, the precise mechanisms underlying alcohol's contribution to cancer pathogenesis remain incompletely understood. This narrative review focuses on the key current literature on the biological pathways through which alcohol may influence the development of breast and ovarian cancer. Key mechanisms discussed include the modulation of estrogen levels, the generation of reactive oxygen species, the production of acetaldehyde, the promotion of chronic inflammation, and the induction of epigenetic changes. Alcohol's impact on estrogenic signaling, particularly in the regulation of estrogen and progesterone, is explored in the context of hormone-dependent cancers. Additionally, the role of alcohol-induced DNA damage, mutagenesis, and immune system modulation in tumor initiation and progression is examined. Overall, this review emphasizes the importance of alcohol as a modifiable risk factor for breast and ovarian cancer and highlights the need for further research to clarify its role in cancer biology.

Exploring the Complex Mechanisms of Isoflavones: From Cell Bioavailability, to Cell Dynamics and Breast Cancer.

In Western countries, the increase in the consumption of soy-derived products raises the population's exposure to isoflavones. These molecules, present in many foods, have numerous effects on the body's cells, including regulation of the transcription and epigenetics, cell signaling, cell cycle, cell growth, apoptosis, and oxidative stress. However, despite the multitude of studies conducted, on these compounds, it remains difficult to draw definitive conclusions regarding their safety or dangerousness in the diet. Indeed, some epidemiological studies highlight health benefits in consuming isoflavone-rich foods, notably by reducing the risk of certain cancers. However, several studies conducted on cell models show that these molecules can have negative effects on cell fate, particularly with regard to proliferation and survival of mammary tumor cells. Isoflavones are mainly genistein, daidzein, formononetin, and biochanin A. These molecules belong to the family of phytoestrogens, which are capable of interacting with both nuclear estrogen receptor, ERα and ERβ, to trigger agonistic and antagonistic effects. Due to their estrogenic properties, isoflavones are suspected to promote hormone-dependent cancers such as breast cancer. This suspicion is based primarily on their ability to bind to ERα in breast cells, thereby altering the signaling pathways that control cell growth. However, study results are sometimes contradictory. Some studies suggest that isoflavones may protect against breast cancer by acting as selective estrogen receptor modulators, while others highlight their potential role in stimulating tumor growth. This review explores the literature on the effects of isoflavones, focusing on their influence on ERα-dependent signaling in breast tumor cells.

Lipid metabolic reprogramming drives triglyceride storage and variable sensitivity to FASN inhibition in endocrine-resistant breast cancer cells.

Lipid metabolic reprogramming is increasingly recognized as a hallmark of endocrine resistance in estrogen receptor-positive (ER+) breast cancer. In this study, we investigated alterations in lipid metabolism in ER+ breast cancer cell lines with acquired resistance to common endocrine therapies and evaluated the efficacy of a clinically relevant fatty acid synthase (FASN) inhibitor. ER+ breast cancer cell lines resistant to Tamoxifen (TamR), Fulvestrant (FulvR), and long-term estrogen withdrawal (EWD) were derived. Global gene expression and lipidomic profiling were performed to compare parental and endocrine resistant cells. Lipid storage was assessed using Oil Red O (ORO) staining. The FASN inhibitor TVB-2640 was tested for its impact on lipid storage and cell growth. 13 C 2 -acetate tracing was used to evaluate FASN activity and the efficacy of TVB-2640. Endocrine resistant cells showed significant enrichment in lipid metabolism pathways and distinct lipidomic profiles, characterized by elevated triglyceride levels and enhanced cytoplasmic lipid droplets. 13 C 2 -acetate tracing revealed increased FASN activity in endocrine resistant cells, which was effectively reduced by TVB-2640. While TVB-2640 reduced lipid storage in most but not all cell lines, this did not correlate with decreased cell growth. Polyunsaturated fatty acids (PUFAs) containing 6 or more double bonds were elevated in endocrine resistant cells and remained unaffected or increased with TVB-2640. Endocrine resistant breast cancer cells undergo a metabolic shift toward increased triglyceride storage and PUFAs with high degrees of desaturation. While TVB-2640 reduced lipid storage in most conditions, it had limited effects on the growth of endocrine resistant breast cancer cells. Targeting specific lipid metabolic dependencies, particularly pathways that produce PUFAs, represents a potential therapeutic strategy in endocrine resistant breast cancer.

Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives.

Sulfatase (STS) and sulfotransferases (SULT) have important role in the biosynthesis and action of steroid hormones. STS catalyzes the hydrolysis of estrone-sulfate (E1-S) and dehydroepiandrosterone-sulfate (DHEA-S), while sulfotransferases catalyze the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate as a sulfate donor. These enzymes control the concentration of active estrogens and androgens in peripheral tissues. Aberant expression of STS and SULT genes has been found in both, benign hormone-dependent diseases and hormone-dependent cancers. The aim of this review is to present the current knowledge on the role of STS and SULT in gynecological cancers, endometrial (EC) and ovarian cancer (OC). EC is the most common and OC the most lethal gynecological cancer. These cancers primarily affect postmenopausal women and therefore rely on the local production of steroid hormones from inactive precursors, either DHEA-S or E1-S. Following cellular uptake by organic anion transporting polypeptides (OATP) or organic anion transporters (OAT), STS and SULT regulate the formation of active estrogens and androgens, thus disturbed balance between STS and SULT can contribute to the onset and progression of cancer. The importance of these enzymes in peripheral estrogen biosynthesis has long been recognized, and this review provides new data on the important role of STS and SULT in the formation and action of androgens, their regulation and inhibition, and their potential as prognostic biomarkers.

Health risk assessment of phthalate esters and polychlorinated biphenyls from marine plastic pollution in coastal areas of Lagos, Nigeria.

Marine plastic pollution, a major public health issue worldwide, releases toxic persistent organic pollutants (POPs) causing endocrine disruption, cancers, and other adverse effects. However, research on these compounds in the Nigerian marine environment is limited. Using a cross-sectional design and incorporating a laboratory component, this study aimed to assess the health risks associated with marine plastic pollution at Orimedu, Idado, and Eleko along the coastline of Lagos, Nigeria. A total of three coastal water and sediment composite samples were collected over 10m from the shore into the ocean at each study area. The samples were analyzed for concentration levels of six phthalate esters (PEs) and 23 polychlorinated biphenyls (PCBs) using gas chromatography/mass spectrometry (GC/MS) and gas chromatography-electron capture detector (GC-ECD) after preparation. Health risk assessment was also computed using risk assessment models developed by the United States Environmental Protection Agency (USEPA). Results obtained were compared to the World Health Organization's (WHO) standards for cancer risk (1.0 × 10-5) and non-cancer risk (≤ 1.0). Eleko had the highest concentrations of both PEs (24.89 ± 0.01mg/L of DIOP) and PCBs (0.06 ± 0.01 of PCB 206-2,2',3,3',4,4'5,5',6-nonachlorobiphenyl) in the water samples, while in the sediment samples, Idado had the highest PE (69.00 ± 0.05 of DIOP) and Orimedu was found with the highest PCB (0.09 ± 0.03 of PCB 180-2,2',3,4,4',5,5'-heptachlorobiphenyl). Most of the PEs and PCBs were above the limits set by the WHO. Further studies are needed to address the health risk assessment of PEs and PCBs, especially in children and adults, in the coastline communities of Lagos.

Epidemiology and Gender Variation in Thyroid Malignancies: A Retrospective Study of a Tertiary Care Center

Abstract Background: Thyroid malignancies are among the most common endocrine cancers, ranking ninth in incidence. In Saudi Arabia, thyroid cancer rates have significantly increased in both genders. Despite the rising incidence, mortality rates have declined. The evolving epidemiology of thyroid malignancies in Saudi Arabia reflects changes in demographics, culture, and clinical practices. This study aims to update the epidemiological data and examine gender variations in thyroid malignancies. Materials and Methods: This retrospective study included cases admitted to an academic tertiary care center from January 2023 to June 2024. Data on demographic variables (gender, age, and nationality) and clinical diagnosis categories (ranging from nondiagnostic to malignant) were collected. Histopathological details of thyroid lesions were also recorded. Clinical, cytological, and histopathological data were as per the Bethesda system, and they were analyzed accordingly. Results: The average age of 300 patients in our study cohort was 45.56 years, with 81.3% of them being female. The majority of patients were Saudi nationals (87.7%). According to the Bethesda system, the most common findings for lesions were benign (category II), followed by malignant (category VI) and atypia of undetermined significance (AUS; category III). Histopathologically, 52.7% showed benign features, with hyperplastic thyroid lesions (20.7%) and follicular adenomas (14.3%) being the most common. The most common malignancy was papillary carcinoma (42.7%). Age-specific analysis revealed differences, with younger patients more likely to have follicular neoplasm/suspicious for follicular neoplasm (category IV) and older patients having a higher risk of malignancy. Other variables including colloid cyst, subacute granulomatous thyroiditis, follicular carcinoma, Hürthle cell type, and medullary carcinoma were not statistically associated with any age group. Conclusion: Our findings are consistent with global trends indicating a significant increase in thyroid cancers, particularly among women. In our cohort, female patients were diagnosed with thyroid cancer nearly four times more frequently than male patients, which is double the commonly reported gender gap. There were statistically significant differences between genders in age groups, malignancies, and histopathological findings, with hyperplastic thyroid lesions and papillary carcinoma being more common in women. We also observed age-related differences in thyroid findings, with younger patients having more follicular neoplasms and older patients having more AUS.

Human Cytochrome P450 Cancer-Related Metabolic Activities and Gene Polymorphisms: A Review.

Cytochromes P450 (CYPs) are heme-containing oxidoreductase enzymes with mono-oxygenase activity. Human CYPs catalyze the oxidation of a great variety of chemicals, including xenobiotics, steroid hormones, vitamins, bile acids, procarcinogens, and drugs. In our review article, we discuss recent data evidencing that the same CYP isoform can be involved in both bioactivation and detoxification reactions and convert the same substrate to different products. Conversely, different CYP isoforms can convert the same substrate, xenobiotic or procarcinogen, into either a more or less toxic product. These phenomena depend on the type of catalyzed reaction, substrate, tissue type, and biological species. Since the CYPs involved in bioactivation (CYP3A4, CYP1A1, CYP2D6, and CYP2C8) are primarily expressed in the liver, their metabolites can induce hepatotoxicity and hepatocarcinogenesis. Additionally, we discuss the role of drugs as CYP substrates, inducers, and inhibitors as well as the implication of nuclear receptors, efflux transporters, and drug-drug interactions in anticancer drug resistance. We highlight the molecular mechanisms underlying the development of hormone-sensitive cancers, including breast, ovarian, endometrial, and prostate cancers. Key players in these mechanisms are the 2,3- and 3,4-catechols of estrogens, which are formed by CYP1A1, CYP1A2, and CYP1B1. The catechols can also produce quinones, leading to the formation of toxic protein and DNA adducts that contribute to cancer progression. However, 2-hydroxy- and 4-hydroxy-estrogens and their O-methylated derivatives along with conjugated metabolites play cancer-protective roles. CYP17A1 and CYP11A1, which are involved in the biosynthesis of testosterone precursors, contribute to prostate cancer, whereas conversion of testosterone to 5α-dihydrotestosterone as well as sustained activation and mutation of the androgen receptor are implicated in metastatic castration-resistant prostate cancer (CRPC). CYP enzymatic activities are influenced by CYP gene polymorphisms, although a significant portion of them have no effects. However, CYP polymorphisms can determine poor, intermediate, rapid, and ultrarapid metabolizer genotypes, which can affect cancer and drug susceptibility. Despite limited statistically significant data, associations between CYP polymorphisms and cancer risk, tumor size, and metastatic status among various populations have been demonstrated. The metabolic diversity and dual character of biological effects of CYPs underlie their implications in, preliminarily, hormone-sensitive cancers. Variations in CYP activities and CYP gene polymorphisms are implicated in the interindividual variability in cancer and drug susceptibility. The development of CYP inhibitors provides options for personalized anticancer therapy.

GWAS and 3D chromatin mapping identifies multicancer risk genes associated with hormone-dependent cancers.

Hormone-dependent cancers (HDCs) share several risk factors, suggesting a common aetiology. Using data from genome-wide association studies, we showed spatial clustering of risk variants across four HDCs (breast, endometrial, ovarian and prostate cancers), contrasting with genetically uncorrelated traits. We identified 44 multi-HDC risk regions across the genome, defined as overlapping risk regions for at least two HDCs: two regions contained risk variants for all four HDCs, 13 for three HDCs and 28 for two HDCs. Integrating GWAS data, epigenomic profiling and promoter capture HiC maps from diverse cell line models, we annotated 53 candidate risk genes at 22 multi-HDC risk regions. These targets were enriched for established genes from the COSMIC Cancer Gene Census, but many had no previously reported pleiotropic roles. Additionally, we pinpointed lncRNAs as potential HDC targets and identified risk alleles in several regions that altered transcription factors motifs, suggesting regulatory mechanisms. Known drug targets were over-represented among the candidate multi-HDC risk genes, implying that some may serve as targets for therapeutic development or facilitate the repurposing of existing treatments for HDC. Our approach provides a framework for identifying common target genes driving complex traits and enhances understanding of HDC susceptibility.

Hormone replacement therapy and non-gynaecological cancers.

There is lack of knowledge and awareness about HRT use in non-gynaecological cancer survivors. The decision to advocate or discourage HRT in such women depends on various factors, including cancer type, hormone sensitivity, and individual patient characteristics. The paucity of available good quality clinical evidence and epidemiological data leads to lack of consensus in such cases. This article aims to address this knowledge gap by conducting a comprehensive qualitative analysis of the existing literature pertaining to HRT use in non-gynaecological cancer survivors. We conducted a literature review. A systematic review was not possible because of lack of good quality research. We excluded case reports. A total of 55 papers were identified and all of these have been referenced. We have presented the inconsistencies and uncertainties in the evidence available from the limited information available from cohort studies. Prescription of HRT in cancer survivors of many hormone dependent non-gynaecological cancers needs careful consideration of histology of the cancer and consideration about liaison with the concerned oncology team.

CDH2 and CDH13 as potential prognostic and therapeutic targets for adrenocortical carcinoma

ABSTRACT Cadherin 2 (CDH2, N-cadherin) and cadherin 13 (CDH13, T-cadherin, H-cadherin) affect the progress and prognoses of many cancers. However, their roles in adrenocortical carcinoma (ACC), a rare endocrine cancer, remain unclear. To decipher the roles of these proteins in ACC and to identify their regulatory targets, we analyzed their expression levels, gene regulatory networks, prognostic value, and targets in ACC, using various bioinformatic analyses. CDH2 was strongly downregulated and CDH13 was strongly upregulated in patients with ACC; the expression levels of these genes affected the prognosis. In 75 patients, the expression of CDH2 and CDH13 was altered by 8% and 5%, respectively. CDH2 and CDH13, as well as their neighboring genes, were predicted to form a complex network of interactions, mainly through coexpression and physical and genetic interactions. CDH2 and its altered neighboring genes (ANGs) mainly affect tumor-related gene expression, cell cycle, and energy metabolism. The regulation of tumor-related integrin function, gene transcription, metabolism, and amide and phospholipid metabolism are the main functions of CDH13 and its ANGs. MiRNA and kinase targets of CDH2 and CDH13 in ACC were identified. CDH13 expression in patients with ACC was positively associated with immune cell infiltration. Anti-PD1/CTLA-4/PD-L1 immunotherapy significantly downregulated the expression of CDH13 in patients with ACC. Foretinib and elesclomol were predicted to exert strong inhibitory effects on SW13 cells by inhibiting the expression of CDH2 and CDH13. These data indicate that CDH2 and CDH13 are promising targets for precise treatment of ACC and may serve as new biomarkers for ACC prognosis.

The Physiological Aspects of Endocrine Disrutors in Reproduction: A Review

Endocrine disruptors are environmental compounds that affect the normal hormones synthesis, secretion, transport, binding, action or elimination. There interference occurs at certain doses of the chemicals and can cause birth anomalies, as well as sexual developmental problems in both males and females. These hormones play significant role in reproduction. Endocrine disruptors are chemical substances which interfere with the natural hormones in the body and thus affect the maintenance of normal cell metabolism. They are also called hormonally active agents, endocrine disrupting chemicals or endocrine disrupting compounds. Biologically, these effects cause obesity, diabetes, reproductive problems as well as hormone sensitive cancers in both male and female. This is because of the release of great quantity of chemical, following the expansion of the industrial revolution which in turn leads to the alteration in the balance of endocrine and reproductive system. Studies in recent times has shown decline in female fecundity and sperm count. Furthermore, in the United States, the average age at menarche, thalarche and sexual development among minors, has speedily progressed, hence the need to identify their place in reproduction and put in control measures to prevent its attendance complications.