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Life (Basel, Switzerland) May 2024Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with high recurrence rates, a high incidence of distant metastases...
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is associated with high recurrence rates, a high incidence of distant metastases and poor overall survival. The aim of this study was to investigate the role of PD-L1, EGFR and AR expression in TNBC promotion and progression. To that end, we analyzed the immunohistochemical expression of these genes in 125 TNBC patients and their relation to clinicopathological parameters and survival. An elevated expression of PD-L1 was significantly correlated with higher tumor and nuclear grade, while a low expression was correlated with loco-regional recurrence without any influence on survival. Contrary to this, the expression of AR showed a positive impact on the DFI and a negative association with tumor grade. Furthermore, PD-L1 and AR demonstrated simultaneous expression, and further co-expression analysis revealed that a positive expression of PD-L1/AR notably correlates with tumor and nuclear grade and has a significant impact on a longer DFI and OS, while a negative PD-L1/AR expression is significantly associated with metastases. Therefore, our results suggest that positive PD-L1/AR expression is beneficial for TNBC patients. In addition, an elevated expression of EGFR contributes to metastases and a worse DFI and OS. In conclusion, we think that low PD-L1/low AR/high EGFR expression followed by high Ki67 expression constitutes a 'high risk' profile of TNBC.
PubMed: 38929666
DOI: 10.3390/life14060682 -
International Journal of Molecular... Jun 2024The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is...
The neuropeptide vasopressin is known for its regulation of osmotic balance in mammals. Arginine vasotocin (AVT) is a non-mammalian homolog of this neuropeptide that is present in fish. Limited information suggested that vasopressin and its homologs may also influence reproductive function. In the present study, we investigated the direct effect of AVT on spermatogenesis, using zebrafish as a model organism. Results demonstrate that AVT and its receptors (, , , and ) are expressed in the zebrafish brain and testes. The direct action of AVT on spermatogenesis was investigated using an ex vivo culture of mature zebrafish testes for 7 days. Using histological, morphometric, and biochemical approaches, we observed direct actions of AVT on zebrafish testicular function. AVT treatment directly increased the number of spermatozoa in an androgen-dependent manner, while reducing mitotic cells and the proliferation activity of type B spermatogonia. The observed stimulatory action of AVT on spermiogenesis was blocked by flutamide, an androgen receptor antagonist. The present results support the novel hypothesis that AVT stimulates short-term androgen-dependent spermiogenesis. However, its prolonged presence may lead to diminished spermatogenesis by reducing the proliferation of spermatogonia B, resulting in a diminished turnover of spermatogonia, spermatids, and spermatozoa. The overall findings offer an insight into the physiological significance of vasopressin and its homologs in vertebrates as a contributing factor in the multifactorial regulation of male reproduction.
Topics: Animals; Zebrafish; Male; Spermatogenesis; Vasotocin; Testis; Receptors, Vasopressin; Zebrafish Proteins; Spermatozoa; Cell Proliferation; Spermatogonia
PubMed: 38928267
DOI: 10.3390/ijms25126564 -
International Journal of Molecular... Jun 2024Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles....
Aging (senescence) is an unavoidable biological process that results in visible manifestations in all cutaneous tissues, including scalp skin and hair follicles. Previously, we evaluated the molecular function of adenosine in promoting alopecia treatment in vitro. To elucidate the differences in the molecular mechanisms between minoxidil (MNX) and adenosine, gene expression changes in dermal papilla cells were examined. The androgen receptor (AR) pathway was identified as a candidate target of adenosine for hair growth, and the anti-androgenic activity of adenosine was examined in vitro. In addition, ex vivo examination of human hair follicle organ cultures revealed that adenosine potently elongated the anagen stage. According to the severity of alopecia, the ratio of the two peaks (terminal hair area/vellus hair area) decreased continuously. We further investigated the adenosine hair growth promoting effect in vivo to examine the hair thickness growth effects of topical 5% MNX and the adenosine complex (0.75% adenosine, 1% penthenol, and 2% niacinamide; APN) in vivo. After 4 months of administration, both the MNX and APN group showed significant increases in hair density (MNX + 5.01% ( < 0.01), APN + 6.20% ( < 0.001)) and thickness (MNX + 5.14% ( < 0.001), APN + 10.32% ( < 0.001)). The inhibition of AR signaling via adenosine could have contributed to hair thickness growth. We suggest that the anti-androgenic effect of adenosine, along with the evaluation of hair thickness distribution, could help us to understand hair physiology and to investigate new approaches for drug development.
Topics: Alopecia; Humans; Male; Receptors, Androgen; Adenosine; Hair Follicle; Signal Transduction; Minoxidil; Female; Animals; Hair
PubMed: 38928239
DOI: 10.3390/ijms25126534 -
International Journal of Molecular... Jun 2024Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary...
Vitamin D is proposed to have a protective effect against cardiovascular disease, though the mechanism is unclear. Vitamin D deficiency is common in polycystic ovary syndrome (PCOS), where it is strongly related to obesity, insulin resistance (IR) and risk of cardiovascular disease. To determine if the inherent pathophysiology of PCOS or vitamin D levels are linked to dysregulation of cardiovascular risk proteins (CVRPs), a study in non-obese women with PCOS and without IR was undertaken. Our hypothesis was that the levels of vitamin D and its active metabolite would be associated with CVRPs comparably in women with and without PCOS. In women with PCOS ( = 29) and controls ( = 29), 54 CVRPs were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement and correlated to 25-hydroxyvitamin D (25(OH)D) and the active 1,25-dihydroxyvitamin D (1,25(OH)D) measured by gold standard isotope-dilution liquid chromatography tandem mass spectrometry. Women with PCOS had comparable IR and systemic inflammation (normal C-reactive protein) to control women, though had higher free androgen index and anti-Mullerian hormone levels. 25(OH)D and 1,25(OH)D levels did not differ between groups. Nine CVRPs were higher in PCOS ( < 0.05) (Galectin-9, Brother of CDO, C-motif chemokine 3, Interleukin-18 receptor-1, Thrombopoietin, Interleukin-1 receptor antagonist protein, Programmed cell death 1 ligand-2, Low-affinity immunoglobulin gamma Fc-region receptor II-b and human growth hormone), whilst 45 CVRPs did not differ. 25(OH)D correlated with five CVRPs in PCOS and one in controls ( < 0.05). Despite the women with PCOS not exhibiting overt systemic inflammation, 9 of 54 CVRPs were elevated, all relating to inflammation, and 5 of these correlated with 25(OH)D suggesting an ongoing underlying inflammatory process in PCOS even in the absence of obesity/IR.
Topics: Humans; Polycystic Ovary Syndrome; Female; Adult; Cross-Sectional Studies; Biomarkers; Vitamin D; Cardiovascular Diseases; Heart Disease Risk Factors; Vitamin D Deficiency; Insulin Resistance; Obesity; Young Adult
PubMed: 38928037
DOI: 10.3390/ijms25126330 -
Biomedicines Jun 2024It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced... (Review)
Review
It is generally assumed that all estrogen-receptor-positive (ER+) breast cancers proliferate in response to estrogen and, therefore, examples of the estrogen-induced regression of ER+ cancers are paradoxical. This review re-examines the estrogen regression paradox for the Luminal A subtype of ER+ breast cancers. The proliferative response to estrogen is shown to depend on the level of ER. Mechanistically, a window of opportunity study of pre-operative estradiol suggested that with higher levels of ER, estradiol could activate the DREAM-MMB (Dimerization partner, Retinoblastoma-like proteins, E2F4, and MuvB-MYB-MuvB) pathway to decrease proliferation. The response of breast epithelium and the incidence of breast cancers during hormonal variations that occur during the menstrual cycle and at the menopausal transition, respectively, suggest that a single hormone, either estrogen, progesterone or androgen, could activate the DREAM pathway, leading to reversible cell cycle arrest. Conversely, the presence of two hormones could switch the DREAM-MMB complex to a pro-proliferative pathway. Using publicly available data, we examine the gene expression changes after aromatase inhibitors and ICI 182,780 to provide support for the hypothesis. This review suggests that it might be possible to integrate all current hormonal therapies for Luminal A tumors within a single theoretical schema.
PubMed: 38927507
DOI: 10.3390/biomedicines12061300 -
Anticancer Research Jul 2024The cytoprotective heat shock protein 27 (HSP27) acts as a protein chaperone, antioxidant, and apoptosis regulator and is involved in cytoskeletal remodeling in prostate...
BACKGROUND/AIM
The cytoprotective heat shock protein 27 (HSP27) acts as a protein chaperone, antioxidant, and apoptosis regulator and is involved in cytoskeletal remodeling in prostate cancer. This study was designed to assess the effect of prostate cancer therapeutics on HSP27 to identify drugs that may benefit from an HSP27 inhibitor combination therapy.
MATERIALS AND METHODS
Cell counting was utilized to assess drug treatment efficiency. Changes in protein levels after drug treatment were assessed using western blot analysis.
RESULTS
Abiraterone, cabazitaxel, docetaxel and enzalutamide significantly reduced cell proliferation in LNCaP and PC3 cells. Treatment with abiraterone and enzalutamide led to a significant reduction in HSP27 protein levels. In contrast, treatment with cabazitaxel and docetaxel did not change the HSP27 protein levels.
CONCLUSION
Treatment with abiraterone and enzalutamide reduces HSP27 protein in an AR-independent manner and thus suppresses HSP27-correlated resistance mechanisms. However, docetaxel and cabazitaxel do not alter HSP27 protein levels, so that taxanes' efficacy may be enhanced by combining them with HSP27-inhibiting drugs.
Topics: Humans; Male; Taxoids; Docetaxel; Phenylthiohydantoin; Benzamides; Nitriles; HSP27 Heat-Shock Proteins; Drug Resistance, Neoplasm; Prostatic Neoplasms; Androstenes; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Molecular Chaperones; Heat-Shock Proteins
PubMed: 38925843
DOI: 10.21873/anticanres.17093 -
Anticancer Research Jul 2024The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However,...
BACKGROUND/AIM
The therapeutic landscape for metastatic castration-resistant prostate cancer (mCRPC) has changed dramatically with the introduction of several novel agents. However, limited data are available to determine whether the introduction of novel agents affected patient characteristics, treatment patterns, and outcomes compared with the period when these agents were not available. The objective of this study was to evaluate the impact of the introduction of novel mCRPC agents on patient characteristics, treatment patterns, and outcomes.
PATIENTS AND METHODS
Two cohorts of Japanese patients diagnosed with mCRPC between 2009 and 2014 (Epoch 1) and 2015 and 2019 (Epoch 2) were retrospectively analyzed.
RESULTS
A total of 125 treatment-naïve mCRPC patients, consisting of 42 patients in Epoch 1 and 83 patients in Epoch 2, were evaluated. We obtained the following results: (i) a dramatic shift in the first-line treatment from docetaxel to androgen receptor axis-targeted agents (ARATs), (ii) an age range expansion for first-line treatment, and (iii) an overall survival (OS) advantage in Eopch 2 compared to Epoch 1. Multivariate analysis in the overall population showed that Epoch 2 and low prostate-specific antigen (PSA) levels at the start of first-line treatment were independent prognostic factors for OS.
CONCLUSION
In real-world mCRPC practice, the introduction of novel agents has improved the prognosis of mCRPC while allowing more patients to receive mCRPC treatment across a broad age range. In addition, low PSA levels at the start of first-line treatment were associated with improved OS, indicating the importance of starting mCRPC treatment while PSA levels are low.
Topics: Humans; Male; Prostatic Neoplasms, Castration-Resistant; Aged; Aged, 80 and over; Retrospective Studies; Middle Aged; Treatment Outcome; Docetaxel; Prostate-Specific Antigen; Neoplasm Metastasis; Antineoplastic Combined Chemotherapy Protocols; Antineoplastic Agents
PubMed: 38925833
DOI: 10.21873/anticanres.17130 -
Molecular Carcinogenesis Jun 2024Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins...
Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptor to which a spider venom latrotoxin is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in urothelial tumorigenesis. In human normal urothelial SVHUC cells, AR overexpression and androgen treatment considerably increased the expression levels of ADGRL3/LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. In SVHUC or SVHUC-AR cells with exposure to a chemical carcinogen 3-methylcholanthrene, LPHN3 activation via ligand (e.g., α-latrotoxin, FLRT3) treatment during the process of the neoplastic/malignant transformation or LPHN3 knockdown via shRNA virus infection induced or reduced, respectively, the oncogenic activity. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated female mice, α-latrotoxin or FLRT3 injection accelerated the development of bladder tumors. Immunohistochemistry in surgical specimens further showed the significantly elevated expression of LPHN3 in non-muscle-invasive bladder tumors, compared with adjacent normal urothelial tissues, which was associated with a marginally (p = 0.051) higher risk of disease recurrence after transurethral resection. In addition, positivity of LPHN3 and AR in these tumors was strongly correlated. These findings indicate that LPHN3 functions as a downstream effector of AR and promotes urothelial tumorigenesis.
PubMed: 38925569
DOI: 10.1002/mc.23783 -
Molecular and Cellular Endocrinology Jun 2024Innate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone...
Innate social behaviors like aggression are modulated by sex steroid hormones such as androgens and estrogens. However, we know little about how the same hormone regulates similar behaviors in both sexes. We investigated the role of androgenic signaling in the regulation of aggression in Astatotilapia burtoni, a social fish in which males and females perform similar aggressive behaviors. We used androgen receptor (AR) α knockout (KO) animals for this study, which was recently shown to be required for male-typical aggression and mating. Surprisingly, ARα KO females did not show deficits in aggression. We also determined that females lacking the other AR, ARβ, showed normal levels of aggression. Blocking both ARs pharmacologically confirmed that neither AR is necessary for aggression in females. However, ARα KO males showed clear deficits in attacks. Thus, in A. burtoni there appears to be a sexual dimorphism in the role of ARα in the control of aggression.
PubMed: 38925266
DOI: 10.1016/j.mce.2024.112319 -
Reproductive Toxicology (Elmsford, N.Y.) Jun 2024Bisphenol A (BPA) is a widespread industrial chemical, used as the key monomer of polycarbonate plastics and epoxy resins. BPA has been detected in human seminal fluid...
Bisphenol A (BPA) is a widespread industrial chemical, used as the key monomer of polycarbonate plastics and epoxy resins. BPA has been detected in human seminal fluid and has been correlated with changes in sperm parameters, crucial in determining male fertility. In this study, semen samples were collected from 100 patients aged 29-47 years undergoing fertility assessment between 2021 and 2023 and analyzed according to WHO guidelines. BPA levels in the seminal plasma were then measured through an enzyme-linked immunosorbent assay (ELISA) and compared to sperm quality metrics. The relative mRNA/miRNA expression of key genes associated to male reproduction, including androgen receptor, miR-34c, miR-21, miR-130a, was then quantified and compared between groups with high or low BPA content. Our results revealed that BPA levels were increased with age and were negatively correlated with sperm counts (p<0.05). The negative correlation remained significant when patients were age-matched. No other relationships between seminal BPA and motility, morphology or DNA fragmentation levels were observed. qPCR analysis showed that androgen receptor mRNA expression was significantly greater in sperm with high seminal BPA (p<0.05). Moreover, we found that the expression of miR-21 and miR-130a was also upregulated in the higher BPA group (p<0.05). These results display a relationship between BPA content in the semen and male fertility parameters, and provide insights into the molecular mechanisms through which BPA may be affecting male reproductive capability. Ultimately, this research can potentially drive changes to guidelines and exposure limits for BPA exposure.
PubMed: 38925230
DOI: 10.1016/j.reprotox.2024.108651