-
Cancers May 2024Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to... (Review)
Review
Triple Negative Breast Cancer (TNBC) is characterized by distinct molecular subtypes with unique biological and clinical features. This systematic review aimed to identify articles examining the differences in the tumor immune microenvironment (TIME) across different TNBC molecular subtypes. Six studies meeting inclusion criteria were analyzed, utilizing gene expression profiling and bioinformatic analyses to classify TNBC samples into molecular subtypes, as well as immunohistochemistry and cell deconvolution methods to characterize the TIME. Results revealed significant heterogeneity in immune cell composition among TNBC subtypes, with the immunomodulatory (IM) subtype demonstrating robust immune infiltration, composed mainly of adaptive immune cells along with an increased density of CTLA-4+ and PD-1+ TILs, high PD-L1 tumor cell expression, and upregulation of FOXP3+ Tregs. A more immunosuppressive TIME with a predominance of innate immune cells and lower levels of tumor-infiltrating lymphocytes (TILs) was observed in luminal androgen receptor (LAR) tumors. In mesenchymal stem-like (MSL) tumors, the TIME was mainly composed of innate immune cells, with a high number of M2 tumor-associated macrophages (TAMs), while the BL and M tumors displayed poor adaptive and innate immune responses, indicating an "immune-cold" phenotype. Differential activation of signaling pathways, genomic diversity, and metabolic reprogramming were identified as contributors to TIME heterogeneity. Understanding this interplay is crucial for tailoring therapeutic strategies, especially regarding immunotherapy.
PubMed: 38893213
DOI: 10.3390/cancers16112094 -
International Journal of Molecular... May 2024The intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response...
The intrinsic subtype of triple-negative breast cancer (TNBC) is based on genomic evaluation. In this study, we report the survival and pathological complete response (pCR) rates of TNBC patients subtyped by IHC and treated with neoadjuvant chemotherapy (NACT). A retrospective cohort of 187 TNBC patients who received NACT between 2008 and 2017 was used, and IHC subtyping was performed on biopsy specimens before chemotherapy. The subtyping revealed predominantly basal-like tumors (IHC-BL, 61%), followed by basal-like immune-suppressed tumors (IHC-BLIS, 31%), mesenchymal tumors (12.5%), luminal androgen receptor tumors (IHC-LAR, 12%), and basal-like immune-activated tumors (IHC-BLIA, 10.9%). The pCR rate varied among subtypes, with IHC-BLIA showing the highest (30.0%) and IHC-LAR showing the lowest (4.5%). IHC-BLIS led in recurrence sites. Overall and disease-free survival analyses did not show significant differences among subtypes, although IHC-BLIA demonstrated a trend toward better survival, and IHC-mesenchymal, worse. Patients who achieved pCR exhibited significantly better disease-free survival and overall survival than non-responders. This study underscores the potential of IHC-based subtyping in TNBC management, highlighting distinct response patterns to neoadjuvant chemotherapy and potential implications for treatment strategies. Further research is warranted to validate these findings and explore tailored therapeutic approaches for specific TNBC subtypes.
Topics: Humans; Triple Negative Breast Neoplasms; Female; Neoadjuvant Therapy; Middle Aged; Adult; Immunohistochemistry; Aged; Retrospective Studies; Biomarkers, Tumor; Treatment Outcome; Disease-Free Survival; Prognosis
PubMed: 38892013
DOI: 10.3390/ijms25115825 -
Communications Biology Jun 2024Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of...
Although low estrogen is considered to suppress uterine endometrial carcinoma, the most cases occur in the postmenopausal stage. After menopause, the production of androgen level also declines. Therefore, to resolve the above enigma, we hypothesize that the postmenopausal decline of androgen is a trigger of its progression. In the present study, to validate this hypothesis, we examine the pathological roles of androgen/AR by analyzing clinical data, culturing endometrioid cancer cell lines, and using murine models. Clinical data show that androgen receptor (AR) expression and serum dihydrotestosterone (DHT) are associated with lower disease-free survival (DFS). DHT suppresses malignant behaviors in AR-transfected human endometrial cancer cells (ECC). In ovariectomized Pten/PR mice, DHT decreases the proliferation of spontaneously developed murine ECC. In AR-transfected human ECC and Pten/PR mice, DHT suppresses FOXP4 expression. FOXP4-overexpressed human ECC increases, while FOXP4-knocked-down ECC shows decreased malignant behaviors. DHT/AR-mediated ECC suppression is restored by FOXP4 overexpression. The high FOXP4 expression is significantly correlated with low postoperative DFS. These findings indicate that the androgen/AR system suppresses the malignant activity of endometrial carcinoma and that downstream FOXP4 is another target molecule. These findings will also impact developments in clinical approaches to elderly health.
Topics: Female; Endometrial Neoplasms; Humans; Animals; Mice; Forkhead Transcription Factors; Receptors, Androgen; Androgens; Cell Line, Tumor; Dihydrotestosterone; Gene Expression Regulation, Neoplastic; Middle Aged; Cell Proliferation
PubMed: 38890503
DOI: 10.1038/s42003-024-06433-w -
Cancer Science Jun 2024Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality...
Prostate carcinoma represents a predominant malignancy affecting the male population, with androgen deprivation therapy (ADT) serving as a critical therapeutic modality for advanced disease states, but it often leads to the development of resistance. Enzalutamide (Enz), a second-generation antiandrogen drug, initially offers substantial therapeutic benefit, but its efficacy wanes as drug resistance ensues. In this study, we found that synaptotagmin 4 (SYT4) is an upregulated gene in enzalutamide-resistant (EnzR) cell lines. The downregulation of SYT4, in combination with enzalutamide therapy, substantially enhances the antiproliferative effect on resistant prostate cancer cells beyond the capacity of enzalutamide monotherapy. SYT4 promotes vesicle efflux by binding to the synaptosome-associated protein 25 (SNAP25), thereby contributing to cell resistance against enzalutamide. The elevated expression of SYT4 is mediated by bromodomain-containing protein 4 (BRD4), and BRD4 inhibition effectively suppressed the expression of SYT4. Treatment with a therapeutic dose of enzalutamide combined with ASO-1, an antisense oligonucleotide drug targeting SYT4, shows promising results in reversing the resistance of prostate cancer to enzalutamide.
PubMed: 38889208
DOI: 10.1111/cas.16239 -
Sexual Medicine Jun 2024The endothelial glycocalyx is an important barrier that protects the structure and function of endothelial cells. Androgen deficiency is a common factor that causes...
BACKGROUND
The endothelial glycocalyx is an important barrier that protects the structure and function of endothelial cells. Androgen deficiency is a common factor that causes structural and functional impairment of endothelial cells.
AIM
To investigate changes in the endothelial glycocalyx in the penile corpus cavernosum of the rat with low androgen status and its relationship with erection function.
METHODS
Eighteen 10-week-old Sprague-Dawley male rats were randomly divided into 3 groups (n = 6 each): sham operation, castration, and castration + testosterone replacement. The maximum intracavernosal pressure/mean arterial pressure of the penis was measured after modeling for 4 weeks. The expression levels of endothelial nitric oxide synthase (eNOS), phospho-eNOS, syndecan 1, heparanase, and nitric oxide in penile cavernous tissue and the serum levels of heparan sulfate, hyaluronic acid, tumor necrosis factor α, and interleukin 6 were determined. Transmission electron microscopy was used to observe the ultrastructure of the endothelial glycocalyx in penile tissue.
OUTCOMES
The thickness of the endothelial glycocalyx in the penile corpus cavernosum of castrated rats was significantly lower than that of the control group.
RESULTS
In the castrated rats, the endothelial glycocalyx thickness, syndecan 1 level, ratio of phospho-eNOS to eNOS, nitric oxide level, and maximum intracavernosal pressure/mean arterial pressure (3 V, 5 V) were significantly lower than those in the sham group ( < .05). The expression of heparanase and the serum levels of tumor necrosis factor α and interleukin 6 were significantly higher in the castrated group than in the sham group ( < .05).
CLINICAL TRANSLATION
Upregulating the expression of the endothelial glycocalyx in the penile corpus cavernosum may be a new method for treating erectile dysfunction caused by low androgen levels.
STRENGTHS AND LIMITATIONS
This study confirms that low androgen status promotes the breakdown of the endothelial glycocalyx. However, further research is needed to determine whether androgens are related to the synthesis of the endothelial glycocalyx.
CONCLUSION
Low androgen status may suppress the level of nitric oxide in the cavernous tissue of the penis via impairment of the endothelial glycocalyx, resulting in inhibited erection function in rats.
PubMed: 38883807
DOI: 10.1093/sexmed/qfae039 -
Journal of the Endocrine Society May 2024The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical... (Review)
Review
The role of estradiol (E2; an estrogen) in men needs to be more appreciated. In this review, we address the clinical situations that allow the study of the clinical consequences of E2 deficiency in men and discuss the effects of restoration of levels of this reproductive steroid hormone. In men with advanced prostate cancer (PCa) undergoing androgen deprivation therapy (ADT), E2 is suppressed along with testosterone, leading to side effects affecting the quality of life. These include hot flashes, arthralgia, fatigue, mood changes, cognition problems, weight gain, bone loss, and increased risk of cardiovascular disease. Transdermal E2 alone for ADT has shown equivalent testosterone suppression compared to gonadotropin-releasing hormone (GnRH) agonists while also preventing estrogen-deficiency side effects, including hot flashes and bone loss. Co-treatment of ADT with fetal estrogen estetrol (E4) has shown significant improvements of estrogen-deficiency symptoms. These observations emphasize the need to raise awareness of the importance of estrogens in men among clinicians and the lay public.
PubMed: 38883397
DOI: 10.1210/jendso/bvae107 -
Oncogene Jun 2024Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors,...
Treatment-induced neuroendocrine prostate cancer (t-NEPC) often arises from adenocarcinoma via lineage plasticity in response to androgen receptor signaling inhibitors, such as enzalutamide. However, the specific regulators and targets involved in the transition to NEPC are not well understood. Plexin D1 (PLXND1) is a cellular receptor of the semaphorin (SEMA) family that plays important roles in modulating the cytoskeleton and cell adhesion. Here, we found that PLXND1 was highly expressed and positively correlated with neuroendocrine markers in patients with NEPC. High PLXND1 expression was associated with poorer prognosis in prostate cancer patients. Additionally, PLXND1 was upregulated and negatively regulated by androgen receptor signaling in enzalutamide-resistant cells. Knockdown or knockout of PLXND1 inhibited neural lineage pathways, thereby suppressing NEPC cell proliferation, patient derived xenograft (PDX) tumor organoid viability, and xenograft tumor growth. Mechanistically, the heat shock protein 70 (HSP70) regulated PLXND1 protein stability through degradation, and inhibition of HSP70 decreased PLXND1 expression and NEPC organoid growth. In summary, our findings indicate that PLXND1 could serve as a promising therapeutic target and molecular marker for NEPC.
PubMed: 38877132
DOI: 10.1038/s41388-024-03081-6 -
Theriogenology Jun 2024The increased LH levels resulting from the absence of negative feedback after castration has been linked to long-term health issues. A need exists for an alternative...
The increased LH levels resulting from the absence of negative feedback after castration has been linked to long-term health issues. A need exists for an alternative contraceptive agent that functions without interfering the LH pathways. This study aimed to develop antibody fragments against the follicular-stimulating hormone receptor (anti-FSHr) using phage-display technology and evaluate its effects on Sertoli cell functions. Phage clones against the extracellular domain of dog and cat FSHr selected from an antibody fragment phagemid library were analyzed for binding kinetics by surface plasmon resonance. Sertoli cells were isolated from testes of adult animals (five dogs and five cats). Efficacy test was performed by treating Sertoli cell cultures (SCCs) with anti-FSHr antibody fragments compared with untreated in triplicates. Expressions of androgen binding protein (ABP), inhibin subunit beta B (IHBB) and vascular endothelial growth factor A (VEGFA) mRNA in SCCs were quantified by RT-qPCR. The results demonstrated that the molecular weight of the purified dog and cat anti-FSHr antibody fragment was 25 kDa and 15 kDa, respectively. Based on protein molecular weight, the antibody fragment of dogs and cats was therefore, so-called single-chain variable fragments (scFv) and nanobody (nb), respectively. The binding affinity with dissociation constant (K) was 2.32 × 10 M and 2.83 × 10 M for dog and cat anti-FSHr antibody fragments, respectively. The cross-binding kinetic interactions between the dog anti-FSHr scFv and the cat ECD of FSHr could not be fitted to the curves to determine the binding kinetics. However, the cross-binding affinity K between the cat anti-FSHr nb and the dog ECD FSHr was 1.75 × 10 M. The mRNA expression of ABP, IHBB and VEGFA in SCCs was less (P < 0.05) in both dogs (12.26, 4.07 and 5.11 folds, respectively) and cats (39.53, 14.07 and 20.29 folds, respectively) treated with anti-FSHr antibody fragments, indicating the Sertoli cell functions were suppressed. In conclusion, this study demonstrated the establishment of species-specific antibody fragments against FSHr in SCCs for dogs and cats. The fragment proteins illustrate potential to be developed as non-surgical contraceptive agent targeting FSHr in companion animals.
PubMed: 38875921
DOI: 10.1016/j.theriogenology.2024.06.005 -
Science (New York, N.Y.) Jun 2024Antimalarial suppresses ovarian androgen synthesis to relieve polycystic ovary syndrome.
Antimalarial suppresses ovarian androgen synthesis to relieve polycystic ovary syndrome.
Topics: Animals; Female; Humans; Mice; Androgens; Antimalarials; Ovary; Polycystic Ovary Syndrome
PubMed: 38870311
DOI: 10.1126/science.adq0328 -
Science (New York, N.Y.) Jun 2024Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic...
Polycystic ovary syndrome (PCOS), a prevalent reproductive disorder in women of reproductive age, features androgen excess, ovulatory dysfunction, and polycystic ovaries. Despite its high prevalence, specific pharmacologic intervention for PCOS is challenging. In this study, we identified artemisinins as anti-PCOS agents. Our finding demonstrated the efficacy of artemisinin derivatives in alleviating PCOS symptoms in both rodent models and human patients, curbing hyperandrogenemia through suppression of ovarian androgen synthesis. Artemisinins promoted cytochrome P450 family 11 subfamily A member 1 (CYP11A1) protein degradation to block androgen overproduction. Mechanistically, artemisinins directly targeted lon peptidase 1 (LONP1), enhanced LONP1-CYP11A1 interaction, and facilitated LONP1-catalyzed CYP11A1 degradation. Overexpression of LONP1 replicated the androgen-lowering effect of artemisinins. Our data suggest that artemisinin application is a promising approach for treating PCOS and highlight the crucial role of the LONP1-CYP11A1 interaction in controlling hyperandrogenism and PCOS occurrence.
Topics: Animals; Female; Humans; Mice; Rats; Androgens; Artemisinins; Cholesterol Side-Chain Cleavage Enzyme; Disease Models, Animal; Hyperandrogenism; Mitochondrial Proteins; Ovary; Polycystic Ovary Syndrome; Proteolysis; Mice, Inbred C57BL; Young Adult; Adult; Rats, Sprague-Dawley; ATP-Dependent Proteases
PubMed: 38870290
DOI: 10.1126/science.adk5382