Search Results (4,691)

Background: The protective effect of physical activity on breast cancer recurrence may be mediated by sex hormone levels. In this study, we examined the association between habitual physical activity and estrogen and androgen plasma levels in postmenopausal women with localised breast cancer. Methods: We conducted a cross-sectional study among 47 postmenopausal women who were breast cancer survivors with estrogen receptor-positive tumours (enrolled at the Medical Oncology Department of University Hospital Dr. Peset, Valencia, Spain). Habitual physical activity was assessed using the International Physical Activity Questionnaire (IPAQ), and a weighted estimate of total physical activity per week (MET∙min∙wk⁻¹) was calculated. Total plasma levels of estrone, 17β-estradiol, progesterone, androstenedione, testosterone, and dehydroepiandrosterone-sulphate (DHEA-sulphate) were measured. Bivariate analyses by the Spearman correlation test were done between physical activity and each hormone concentration. Multivariate analyses (linear regression) using concentration of each hormone as the dependent variable and physical activity, age, marital status, BMI, Charlson Comorbidity Index, tumour stage, previous radiotherapy, or previous chemotherapy as predictor variables. Results: Estrone concentration was positively and significantly correlated with BMI (ρ = 0.332, p = 0.022), but no other correlations were found between BMI and the other hormone concentrations, nor were concentrations of any hormone associated with age or Charlson Comorbidity Index (p > 0.05 in all cases). Physical activity was significantly and inversely correlated with estrone concentration (ρ = −0.308; p = 0.035). Linear regression analysis confirmed a statistically significant association between estrone concentration and BMI and physical activity, after adjusting for all potential confounders (for BMI: standardised β coefficient = 0.407; non-standardised β coefficient = 1.054; t = 2.898; p = 0.006; 95% CI for non-standardised beta: 0.318- to 1.790; for physical activity: standardised β coefficient = −0.300; non-standardised β coefficient = −0.005; t = −2.135; p = 0.039; 95% CI for non-standardised beta: −0.010- to 0.000). Conclusions: The relationship between estrone concentration and physical activity may be further explored as a biomarker for evaluating the protective effect of physical activity against breast cancer recurrence in women receiving anti-estrogen therapies. Full article

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2′-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin–eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy. Full article

Maternal nutrition during critical windows of development plays a pivotal role in shaping long-term disease susceptibility, including cancer risk. This study investigated whether maternal exposure to lipotropes (methyl donor nutrients) during pregnancy and lactation modulates gene expression in 7,12-dimethylbenzanthracene (DMBA)-induced mammary tumors in adult female offspring. Timed-pregnant Sprague-Dawley rats were fed with either a control or lipotrope-supplemented diet, with or without vitamin B6. Female offspring were exposed to DMBA at puberty, and mammary tumors were evaluated histologically and molecularly. DMBA-induced tumors displayed ductal carcinoma in situ-like morphology and significant upregulation of fetal mammary developmental genes (Tbx2 and Tbx3), the tumorigenesis-associated gene Tp53, and key epigenetic regulators (Hdac1, Dnmt1, and Mthfr). Estrogen receptor 1 (Esr1) mRNA expression also showed a significant increase. Maternal lipotropes supplementation significantly attenuated the expression of these genes in offspring tumors. Collectively, these findings demonstrate that maternal methyl donor nutrition modulates tumor-associated gene expression patterns, potentially by limiting the reactivation of developmental and epigenetic pathways in adulthood. This study highlights maternal nutrition as a modifiable early-life factor with important implications for long-term health programming. Full article

Background/Objectives: Vasomotor symptoms (hot flashes) affect 70–80% of menopausal women, significantly impairing quality of life. Current treatments include hormone therapy, which is contraindicated for many patients, and non-hormonal alternatives with limited efficacy or adverse effects. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, has emerged as a potential therapeutic candidate due to its interaction with the endocannabinoid system. This study aimed to investigate whether a standardized Cannabis sativa extract containing isolated CBD attenuates heat dissipation in ovariectomized rats, a preclinical model of estrogen deficiency. Methods: Female Wistar rats were randomly assigned to sham-operated vehicle-treated (SHAM-V), ovariectomized vehicle-treated (OVX-V), or ovariectomized CBD-treated (OVX-CBD; 10 mg/kg/day, oral gavage) groups. Treatment began on postoperative day 2 and continued for 21 days. Tail-skin temperature, a surrogate marker of heat dissipation, was assessed by infrared thermography on day 14. Energy metabolism was evaluated by indirect calorimetry on day 21. Uterine weight was measured as a biomarker of estrogen depletion. Results: Ovariectomy significantly increased tail temperature compared to SHAM-V. CBD treatment completely prevented this effect, with OVX-CBD animals exhibiting thermographic profiles similar to SHAM-V. Uterine atrophy was not reversed by CBD. No differences in the calorimetry parameter were observed among groups. Conclusions: This study provides novel preclinical evidence that cannabidiol attenuates ovariectomy-induced heat dissipation in rats, without detectable effects on uterine weight or metabolic parameters. These findings suggest that CBD may represent a potential non-hormonal approach for the management of menopausal vasomotor symptoms; however, further studies are required to elucidate the underlying mechanisms and to determine its translational and clinical relevance. Full article

Uterine fibroids (leiomyomas) are common benign smooth muscle tumors that impose substantial symptom burden and healthcare costs worldwide. Although uterine fibroid (leiomyoma) pathogenesis is multifactorial, hypoxia has emerged as a key feature of the uterine fibroid (leiomyoma) microenvironment, particularly within poorly perfused tumor cores. Hypoxia-inducible factor-1α (HIF-1α) is a central transcriptional regulator of cellular adaptation to low oxygen and coordinates downstream programs that support angiogenesis, metabolic reprogramming, cell survival, and extracellular matrix (ECM) remodeling. In uterine fibroids (leiomyomas), these HIF-1α–dependent processes intersect with steroid hormone signaling, growth factor pathways, inflammatory mediators, and redox imbalance, together promoting tumor persistence and progressive fibrosis. This review synthesizes the molecular regulation of HIF-1α, highlights major HIF-linked effector pathways relevant to uterine fibroid (leiomyoma) biology, and emphasizes mechanistic crosstalk with estrogen- and progesterone-responsive signaling, TGF-β/SMAD-driven fibrosis, NF-κB-mediated inflammation, and metabolic checkpoint pathways including mTOR and AMPK. Finally, we evaluate emerging therapeutic strategies that target HIF-1α directly or indirectly through upstream regulators. Full article

Background/Objectives: Outcome prediction in patients with estrogen (ER)-positive metastatic breast cancer (MBC) remains challenging. We investigated whether circulating tumor cell (CTC) count adds prognostic value in ER-positive MBC using immunohistochemical (IHC) or 16α-[¹⁸F]-fluoro-17β-estradiol (FES)-PET imaging. Methods: Patients with newly diagnosed non-rapidly progressive MBC receiving first-line endocrine monotherapy, with ER-positive IHC (biopsy) or FES-PET and available CTC count, were included. Associations of CTC count and CTC-ER status based on ESR1 mRNA expression with progression-free survival (PFS) and overall survival (OS) were analyzed, and the added prognostic value of CTC count (<5 vs. ≥5/7.5 mL) beyond a positive ER result was assessed. Results: In patients with ER-positive IHC (n = 98) or FES-PET (n = 99) out of 106 endocrine-treated patients, ≥5 CTCs were associated with shorter PFS (HR 1.86; p = 0.0047 and 1.75; p = 0.011) and OS (HR 3.19 and 3.22; both p < 0.01), respectively, compared with <5 CTCs. Adding CTC count to ER-positive IHC or FES-PET improved prognostic accuracy for PFS (p = 0.006 and 0.012) and OS (both p < 0.001). CTC-ER status (ESR1 RNA) was not associated with outcomes. Conclusions: CTC count adds prognostic value to PET- or biopsy-based ER analysis in endocrine-treated MBC. Full article

Zearalenone (ZEA) is an estrogenic Fusarium mycotoxin widely contaminating feed and feedstuffs, and posing significant risks to animal health. This preliminary study aimed to evaluate the toxicological effects of dietary exposure to purified ZEA at doses ranging from below to above the Chinese regulatory limit (0.15 mg/kg) in weaned female piglets. Twenty piglets were randomly assigned to five groups (four piglets per group) receiving 0, 0.075, 0.15, 0.3, or 0.6 mg/kg ZEA for 42 days. Results suggested that ZEA promoted systemic oxidative stress, evidenced by decreased serum total antioxidant capacity (T-AOC) and increased malondialdehyde (MDA) content in liver across all doses, and in jejunal mucosa at ≥0.15 mg/kg (p < 0.01). Growth performance declined only at 0.6 mg/kg during days 29–42 (p < 0.01), while hemoglobin (HGB) levels (p < 0.01) and ileal villus height (p < 0.05) were reduced at all doses. ZEA also caused inflammatory dysregulation, as evidenced by decreased interleukin-4 (IL-4) levels in serum, liver, and intestinal tissues across all doses (p < 0.01), and disrupted reproductive hormones even at 0.075 mg/kg, as indicated by suppressed serum luteinizing hormone (LH) levels (p < 0.01), which progressed to histopathological damage in uterine and ovarian tissues at higher doses. These preliminary findings, together with significant correlations between oxidative stress markers and multi-organ parameters, suggest that low doses of purified ZEA may induce systemic oxidative stress and subclinical multi-organ toxicity in weaned female piglets, highlighting the need to incorporate redox status into risk assessment and to explore potential antioxidant-based mitigation strategies. However, given the small sample size, these results should be interpreted with caution and warrant validation in larger samples. Full article

Hormonal contraception is used by hundreds of millions of women worldwide and remains one of the most effective reversible methods of pregnancy prevention. Cardiovascular (CV) safety concerns, particularly venous thromboembolism (VTE), ischemic stroke, myocardial infarction, and blood pressure elevation, are important considerations when choosing forms of contraception. Estrogen-containing combined hormonal contraceptives (CHCs) increase the relative risk of VTE; however, among healthy young nonsmokers, absolute event rates remain low. Risk is strongly modified by estrogen dose, progestin type, route of administration, and individual factors such as age, smoking, migraine with aura, hypertension, obesity, inherited thrombophilia, the postpartum period, and concomitant prothrombotic medications. Progestin-only contraceptives and levonorgestrel-releasing intrauterine systems (LNG-IUSs) generally show a more favorable thrombotic profile and are preferred options for women with contraindications for estrogen. This review summarizes current evidence on the method-specific CV risks of hormonal contraception, highlights the mechanisms underlying these effects, and provides practical guidance for clinical decision-making. Full article

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with increasing incidence linked to obesity and metabolic dysfunction. While early-stage EC is often curable, advanced and recurrent disease remains difficult to treat due to resistance and limited therapeutic options. Natural products derived from traditional Chinese medicine have attracted attention as complementary strategies in EC management. These compounds exhibit multi-target effects, including modulation of estrogen signaling, inhibition of proliferation, induction of apoptosis, and regulation of immune and inflammatory pathways. This review summarizes current evidence on natural products in EC, integrating preclinical findings, emerging clinical data, and mechanistic insights from molecular and systems biology approaches. Key challenges, including variability, bioavailability, and insufficient clinical validation, are discussed. Future directions emphasize the integration of natural products into precision oncology frameworks. Full article

Testicular tumors are the most common neoplasms of the canine male reproductive tract, corresponding to approximately 25% of all tumors in intact males. A large percentage of cases are characterized by one of three main tumor types: seminomas, interstitial Leydig cell tumors, or Sertoli cell tumors. Clinical importance is primarily associated with endocrine activity rather than malignant behavior; orchiectomy is the treatment of choice for most canine testicular cancers. Endocrine activity, particularly estrogen secretion, may result in feminization syndrome and, in severe cases, bone marrow suppression. The diagnostic approach combines physical examination, ultrasonography with hormonal assessment using endocrine testing (testosterone, estradiol, and T:E ratio), and/or tissue level evidence of the estrogen effect (preputial cytology). Management is centered on orchiectomy; unilateral surgery may be considered when the contralateral testis is clinically and ultrasonographically normal and when preservation of reproductive capacity or working ability is still a priority. Dogs with hormonally active tumors benefit from postoperative hematologic and endocrine monitoring. Recent advances in immunohistochemistry (IHC), such as Ki-67 and inhibin-α markers, and imaging techniques are improving tumor characterization and individualized clinical decision making. Full article

Background/Objectives: The treatment of gynecologic malignancies has moved towards a precision medicine model with an approach to prognostication and management based on biomarker testing. The objective of this review is to describe the current landscape of biomarker testing in gynecologic cancer including clinical implications and the approach to testing. Methods: A review of the literature was performed that included published clinical trials which utilized biomarker testing as part of inclusion/exclusion criteria, prospective trials that addressed the application and scoring of biomarkers utilized in gynecologic cancers, prospective clinical trials that utilized biomarker findings to determine management, and national or society guidelines for the scoring of biomarkers and treatment of gynecologic cancers. Findings: The use of biomarker testing as part of the management of gynecologic cancers is the standard of care for both treatment and prognostication. In endometrial cancer, biomarker testing has been incorporated into the staging system and impacts treatment in both the upfront and recurrent setting. Specific biomarkers of interest for endometrial cancer include estrogen receptor (ER), progesterone receptor (PR), DNA Polymerase Epsilon (POLE), mismatch repair proteins (MMR), and Human Epidermal growth factor Receptor-2 (HER2). In ovarian cancer, biomarker testing is primarily utilized in the recurrent setting to guide management of platinum-resistant ovarian cancer with a specific focus on targeted therapy utilizing antibody drug conjugates (ADCs) and immunotherapy. Immunotherapy has become an important component of therapy for cervical cancer and Programmed death-ligand 1 (PD-L1) testing is a key biomarker in determining treatment. Conclusions: The utilization of appropriate assays and processes to accurately assess the status of biomarkers in the pathology laboratory is crucial to the treatment of gynecologic malignancies in the precision medicine era. Full article

Background: While the prognostic and predictive value of tumor cell–derived features such as grade, estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) status, and Ki67 index is well established in breast cancer, less is known about the prognostic role of tumor stroma. This study aimed to evaluate stromal parameters in HER2-positive breast cancer patients treated with adjuvant trastuzumab. Material and methods: The study included 224 patients (T ≥ 1, N ≥ 0, M0) who underwent radical treatment followed by adjuvant chemotherapy, hormone therapy (if ER/PR-positive), and trastuzumab. The following histological and immunohistochemical parameters were analyzed: stroma type, tumor-infiltrating lymphocytes (TILs), eosinophils, neutrophils, central area of fibrosis, necrosis, and programmed cell death protein ligand 1 (PD-L1) expression in tumor and stromal cells. Results: Low TILs percentage (≤50%) was associated with lower tumor grade (G2) (p = 0.013) and ER/PR positivity (p = 0.001). Tumors lacking PD-L1 expression had a lower percentage of TILs (p < 0.001), less frequently exhibited tumor-associated neutrophilia (p = 0.019), and more often presented with desmoplastic stroma (p < 0.001). The following parameters were associated with prognosis: TILs percentage, stroma type, and PD-L1 expression. High TILs percentage (>50%) was an independent positive prognostic factor. Conclusions: In patients with HER2-positive breast cancer treated with adjuvant trastuzumab, the percentage of TILs, stroma type, and PD-L1 expression are prognostically relevant. Specifically, a TILs percentage >50% independently predicts favorable outcomes. Routine evaluation of stromal features may provide additional prognostic information and support treatment planning. Full article

Endometriosis is a chronic estrogen-dependent disorder affecting approximately 10% of women of reproductive age. Increasing epidemiological and molecular evidence indicates that it may represent a precursor condition for a subset of ovarian malignancies collectively defined as endometriosis-associated ovarian cancer (EAOC), predominantly endometrioid and clear cell carcinomas. Malignant transformation is driven by the interplay between chronic inflammation, oxidative stress, and local hyperestrogenism within the endometriotic microenvironment. Recurrent hemorrhage and persistent immune activation further promote genomic instability and clonal expansion. Shared somatic mutations have been identified in both atypical endometriosis and adjacent carcinomas, supporting a model of stepwise tumorigenesis. Dysregulation of signaling pathways and epigenetic mechanisms, including microRNA alterations, further contribute to tumor development. Although the absolute risk of malignant transformation remains low, women with ovarian endometriosis and deep infiltrating disease show an increased risk of ovarian cancer. EAOC is frequently diagnosed at earlier stages and generally demonstrates a more favorable prognosis than high-grade serous carcinoma, although clear cell histotypes may exhibit chemoresistance and distinct molecular vulnerabilities. This review summarizes current evidence on the pathogenesis, molecular mechanisms, and clinical implications of EAOC, highlighting future strategies for risk stratification and personalized surveillance. Full article

Background: Breast cancer brain metastases (BCBMs) are clinically challenging, and treatment decisions are influenced by tumor biology. Because receptor profiles may differ between primary breast tumors and brain metastases and brain biopsy may be impractical, non-invasive imaging biomarkers may provide useful biologic correlates. We evaluated whether diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC) histogram metrics from BCBM were associated with primary tumor estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status; the Ki-67 proliferation index; and luminal status. Methods: This retrospective exploratory single-center study included 72 adults with BCBM who underwent standardized 1.5T brain magnetic resonance imaging. The largest lesion in each patient was segmented on ADC maps in FireVoxel. ADC histogram features, including percentiles, were extracted. Using primary tumor biomarker status as the reference, candidate metrics were screened by univariable logistic regression. Parsimonious multivariable models included age, log-transformed lesion volume, and a single selected ADC percentile scaled by ×10. Discriminatory performance was assessed using area under the receiver operating characteristic curve (AUC); thresholds were derived with the Youden index. No external validation was performed. Results: Low-percentile ADC metrics were associated with ER positivity, PR positivity, and luminal disease, whereas no meaningful ADC histogram discrimination was observed for HER2. In multivariable models, ADC10×10 predicted ER positivity (odds ratio [OR] 0.441; AUC 0.847) and PR positivity (OR 0.478; AUC 0.819). Ki-67 positivity was best predicted by ADC75×10 (OR 3.095; AUC 0.905), although this finding should be interpreted cautiously. Luminal status (non-luminal vs. luminal) was predicted by ADC10×10 (OR 2.251; AUC 0.832). Conclusions: ADC histogram analysis from DWI in BCBM showed exploratory associations with primary tumor hormone receptor status and luminal subtype, but not HER2. These findings support ADC histogram features as candidate imaging biomarkers, but the Ki-67 result and all model performance estimates require cautious interpretation and independent external validation in multicenter cohorts. Full article

Background: Endocrine therapy with tamoxifen remains a cornerstone in the treatment of estrogen receptor-positive (ER+) breast cancer; however, the emergence of resistance to its active metabolites, 4-hydroxytamoxifen (4-OHTAM) and Endoxifen, represents a major clinical limitation. Increasing evidence suggests that drug efflux transporters, redox-adaptive signaling, and translational control mechanisms may converge to promote chemoresistance. This study aimed to investigate the coordinated expression patterns of ABCC transporters, the eukaryotic initiation factor 4F (eIF4F) complex, and NRF2 signaling in tamoxifen-metabolite-resistant MCF-7 breast cancer cells. Methods: MCF-7 cell variants resistant to 4-OHTAM (Variant B) or Endoxifen (Variant C) were established through prolonged drug exposure. Cytotoxicity assays assessed cellular viability and chemoresistance. Protein expression and molecular interactions were analyzed using Western blotting and co-immunoprecipitation. Flow cytometry was employed to evaluate transporter-associated fluorescence intensity. In silico molecular docking was performed to estimate the binding affinity of tamoxifen metabolites to ABCC transporters. Results: Endoxifen-resistant cells exhibited the most pronounced chemoresistant phenotype. Analysis of ABCC transporters revealed modest but consistent increases in fluorescence intensity across resistant variants; however, these differences did not reach statistical significance. Dysregulation of the eIF4F complex was observed, with increased eIF4E and reduced eIF4A levels, suggesting altered translational control associated with resistant phenotypes. Increased NRF2 protein expression was detected in resistant variants, consistent with enhanced redox-adaptive capacity. Analysis of ABCC transporters revealed modest but consistent increases in fluorescence intensity across resistant variants; however, these differences did not reach statistical significance. Molecular docking demonstrated strong binding affinity between Endoxifen and ABCC2, supporting a potential role for transporter-mediated efflux. Conclusions: Tamoxifen-metabolite resistance in ER+ breast cancer is associated with coordinated trends in ABCC transporter-associated signals, altered eIF4F complex expression, and sustained NRF2 signaling. These findings suggest the presence of a multifactorial adaptive network that may contribute to endocrine resistance. Targeting components of this network warrants further mechanistic investigation. Full article