Search Results (551)

Estrogen receptor-positive (ER⁺) breast cancer represents the most prevalent molecular subtype of breast cancer, characterized by hormone-dependent growth, relatively indolent progression, and a pronounced tendency to metastasize to bone. While endocrine therapies remain the cornerstone of treatment, a significant proportion of ER⁺ tumors eventually develop resistance, culminating in distant metastases—most frequently to the bone. Bone metastasis substantially compromises patient survival and quality of life, highlighting the critical need to elucidate its molecular underpinnings. Recent multi-omics and mechanistic studies have shed light on the complex interplay between tumor-intrinsic signaling pathways, such as dysregulated ER signaling, PI3K/AKT/mTOR, TGF-β, and Hippo pathways, and the bone microenvironment, including osteoclast activation, immune suppression, and stromal remodeling. This review systematically summarizes the current understanding of the molecular mechanisms driving bone metastasis in ER⁺ breast cancer, with a particular focus on tumor–bone microenvironment crosstalk and key regulatory pathways. Additionally, we discuss recent advances in therapeutic strategies, encompassing next-generation endocrine therapies, CDK4/6 inhibitors, bone-targeted agents, and pathway-specific inhibitors. Together, these insights pave the way for more effective and personalized interventions against ER⁺ breast cancer with bone involvement. Full article

In recent years, the incidence of breast cancer has increased significantly; therefore, much attention is being paid to research on natural plant-based raw materials in the treatment and prevention of cancer as well as in the treatment of antibiotic-resistant infections. Therefore, Chlorella vulgaris algae extract and indole-3-acetic acid (IAA)—a plant hormone with potential anticancer and antimicrobial properties—were selected for the study. The main objective was to evaluate the effect of algae extract and IAA on the proliferation of cells from three different breast cancer lines: MCF-7, ZR-75-1, and MDA-MB-231. In addition, an analysis of apoptosis and oxidative stress parameters in cancer cells was performed, as well as an assessment of IAA toxicity towards E. coli, S. aureus, and C. albicans. The results obtained allow us to conclude that the extract is effective against estrogen-dependent cells, while the effect of IAA alone varies depending on the microorganism studied, the cell line analyzed, and the concentration used. The extract in selected concentrations induces apoptosis and activates oxidative stress mechanisms, while IAA exhibits cytotoxicity at higher concentrations and stimulates proliferation at lower concentrations. This indicates the need to investigate the mechanisms of action of both Chlorella vulgaris algae extract and IAA in cancer and bacterial cells. Full article

Follicle-stimulating hormone receptor (FSHR) is expressed on the plasma membrane of granulosa cells in the ovarian follicles. FSHR is involved in the development and maturation of Graafian follicles, along with granulosa proliferation and estrogen synthesis. There are two well-characterized non-synonymous single-nucleotide gene polymorphisms in the exon 10 of the human FSHR gene, namely rs6165 (c.919G>A, Ala307Thr) and rs6166 (c.2039A>G, Ser680Asn). Recent research clarifies the association of rs6165/rs6166 with susceptibility to infertility-associated ovarian diseases, ranging from polycystic ovarian syndrome, premature ovarian insufficiency, endometriosis, to ovarian cancer, along with response/resistance to ovulation induction/ovarian stimulation with clomiphene citrate, letrozole, metformin, FSH preparations, and adjunctive growth hormone in infertility treatment. This narrative review aims to update the knowledge on the relationship among rs6165/rs6166, infertility etiology, and differential responses to oral ovulation induction agents, FSH preparations, and adjunctive growth hormone. The re6165/rs6166 genotype-guided choice of individualized ovulation stimulation preparations has great potential to reduce unexpected poor or high ovarian responses in ovulation induction and ovarian stimulation and improve clinical outcomes in reproductive medicine. Current evidence is insufficient, and further studies are warranted to ascertain its potential for clinical implementation. Full article

Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy. Full article

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have transformed the treatment landscape for estrogen receptor-positive (ER+) breast cancer, yet resistance remains a major clinical challenge. Although CDK4/6i induce G₁ arrest and therapy-induced senescence (TIS), the exact nature of this senescent state and its contribution to resistance are not well understood. To explore this, we developed palbociclib- (2PR, 9PR, TPR) and abemaciclib- (2AR, 9AR, TAR) resistant ER+ breast cancer sublines through prolonged drug exposure over six months. Resistant cells demonstrated distinct phenotypic alterations, including cellular senescence, reduced mitochondrial membrane potential, and impaired glycolytic activity. Cytokine profiling and enzyme-linked immunosorbent assay (ELISA) validation revealed a non-canonical senescence-associated secretory phenotype (SASP) characterized by elevated growth/differentiation factor 15 (GDF-15) and serpin E1 (plasminogen activator inhibitor-1, PAI-1) and absence of classical pro-inflammatory interleukins, including IL-1α and IL-6. IL-8 levels were significantly elevated, but no association with epithelial–mesenchymal transition (EMT) was observed. Resistant cells preserved their epithelial morphology, showed no upregulation of EMT markers, and lacked aldehyde dehydrogenase 1-positive (ALDH1+) stem-like populations. Additionally, Regulated upon Activation, Normal T-cell Expressed, and Secreted (RANTES) was strongly upregulated in palbociclib-resistant cells. Together, these findings identify a distinct, non-canonical senescence phenotype associated with CDK4/6i resistance and may provide a foundation for identifying new vulnerabilities in resistant ER+ breast cancers through targeting SASP-related signaling. Full article

Heracleum sosnowskyi Manden., or H. sosnowskyi, of the Apiaceae was first cultivated in the USSR in 1947 as a potential fodder plant. Due to the development of cold-resistant cultivars and the characteristics of H. sosnowskyi, it quickly became feral. As a result, H. sosnowskyi began to spread as an aggressive invasive species in the 1970s and 1980s. By the 90s it had become an ecological disaster. As well as forming monocultures and displacing native species, H. sosnowskyi contains furanocoumarins, photosensitizing compounds that increase skin sensitivity to ultraviolet rays and cause severe burns. In addition, furanocoumarins have cytotoxic, genotoxic, mutagenic and estrogenic effects. H. sosnowskyi also contains essential oils, which are particularly active during flowering and can irritate the mucous membranes of the eyes and respiratory tract, as well as cause allergic reactions in the form of bronchospasm in people with asthma and hypersensitivity. When released in high concentrations, these biologically active compounds have an allelopathic effect on native plant species, displacing them and reducing biodiversity. As H. sosnowskyi is not native; the biologically active compounds it secretes have a xenobiotic effect, causing serious damage to the ecosystems it occupies. However, in parallel with these negative properties, furanocoumarins have been found to be effective in the treatment of cancer and skin diseases. Furanocoumarins possess antimicrobial antioxidant osteo- and neuroprotective properties. Essential oils containing octyl acetate, carboxylic acid esters, and terpenes can be used in the pharmaceutical industry as antiseptic and anti-inflammatory agents. Additionally, essential oils can be used as biofumigants and natural herbicides. A comprehensive approach allows H. sosnowskyi to be viewed in two ways. On the one hand, it is an aggressive alien species that causes significant damage to ecosystems and poses a threat to human health. On the other hand, it is a potentially valuable natural resource whose biomass can be used within the principles of the circular economy. It is hoped that the use of H. sosnowskyi for economic interests can be a partial compensation for the problem of its aggressive invasion, which is of anthropogenic origin. Full article

Background: Genetic studies have found that a germline BRCA1 gene mutation is the origin of highly increased cancer risk. Clinical studies have suggested that increased cancer risk in type-2 diabetes may be attributed to unhealthy lifestyle factors and bad habits. Purpose: Patients with either BRCA1 gene mutation or type-2 diabetes similarly exhibit increased cancer risk, insulin resistance, and fertility disorders. It was suggested that these three alterations derive from a common genomic failure, and its recognition may shed light on the unsolved secret of cancer. Results: (1) Germline mutations on ESR1, BRCA1, and CYP19A genes encoding estrogen receptor alpha (ERα), genome safeguarding BRCA1 protein, and CYP19 aromatase enzyme cause genomic instability. BRCA1 and ESR1 gene mutations specifically cause breast cancer, while error in the CYP19A gene leads to cancers in the endometrium, ovaries, and thyroid. (2) ERα, BRCA1, and CYP19 aromatase proteins are transcription factors creating the crucial DNA stabilizer circuit driven by estrogen regulation. Liganded ERα drives a second regulatory circuit to also control cell proliferation, in partnership with various growth factors. In a third regulatory circuit, liganded ERα drives cellular glucose supply in close interplay with insulin, IGF-1, and glucose transporters. (3) Impaired expression or activation of each transcription factor of the triad leads to defective estrogen signaling and endangers regular cell proliferation, insulin sensitivity, and fertility. (4) Impaired estrogen signaling caused by either genetic or lifestyle factors alarms the hypothalamus, which issues neural and hormonal commands throughout the body to restore estrogen signaling. (5) When the compensatory actions cannot restore estrogen signaling, the breakdown of genomic regulation leads to cancer initiation. (6) Lifestyle factors that upregulate estrogen signaling decrease cancer risk, while downregulating estrogen signaling increases it. Conclusions: Increased cancer risk, insulin resistance, and infertility all originate from defective estrogen signaling. Full article

Zearalenone (ZEN) is a thermostable, lipophilic, non-steroidal estrogenic mycotoxin produced by Fusarium spp. that persistently contaminates food and feed. Its strong estrogenic activity and resistance to conventional detoxification strategies pose significant threats to food safety and human and animal health. Conventional physical and chemical degradation methods often compromise nutritional quality and leave toxic residues. Here we report the engineering of a novel Clonostachys rosea lactone hydrolase, Cr2zen, for efficient ZEN degradation in Pichia pastoris under mild conditions. Native Cr2zen exhibited a protein concentration of 0.076 mg/mL, achieving a degradation rate of approximately 17.9% within 30 min, with kinetic parameters of K_m 75.9 µM and V_max 0.482 µmol/L/s at 30 °C and pH 8.0. By integrating signal peptide screening and codon optimization, we identified Ser-Cr2 as the most effective variant, achieving a rapid 81.53% degradation of 10 ppm ZEN under mild conditions. Fed-batch cultivation in a 7.5 L bioreactor resulted in high cell densities of OD₆₀₀ 332.8 for Ser-Cr2 and 310.8 for Oser-Cr2, with extracellular protein concentrations of 0.62 and 0.79 g/L, respectively. The results demonstrate that signal peptide engineering and codon optimization substantially improved the production of lactone hydrolase in P. pastoris. This study establishes a scalable ZEN degradation under mild conditions in P. pastoris and outlines a strategy to integrate protein and process engineering for enhanced enzymatic mycotoxin degradation. Full article

Introduction: We previously showed that baboon offspring born to mothers deprived of estrogen during the second half of gestation exhibited insulin resistance prior to and after the onset of puberty. Moreover, the size of skeletal muscle myofibers and the number of microvessels important for delivery of insulin/glucose to myofibers were lower in near-term fetuses deprived of estrogen during pregnancy, and myofiber capillarization remained reduced in post-pubertal offspring deprived of estrogen in utero. However, it remains to be determined whether skeletal muscle size is restored to normal in animals deprived of estrogen in utero after the onset of puberty/gonadal estrogen production. Methods: To answer this question, the current study quantified the size and number of slow and fast fibers in biopsies of vastus lateralis skeletal muscle obtained from post-pubertal female baboon offspring 9–12 years old, born to mothers who were untreated (n = 7) or treated during the second half of gestation with letrozole (n = 6; suppressed maternal and fetal estrogen by >90%) or letrozole plus estradiol benzoate (n = 3). Results: Results indicated that skeletal muscle slow and fast fiber growth in female offspring appeared to occur by hypertrophy and that respective size of fibers after the onset of puberty was similar in offspring born to mothers who were untreated or deprived of estrogen in utero. Conclusions: Postnatal myofiber hypertrophy likely reflects the impact of the pubertal surge in and continued exposure of offspring myofibers to ovarian estrogen and is restored to normal in post-pubertal female offspring deprived of estrogen in utero. Full article

Background: Endometriosis is a chronic inflammatory disorder that affects approximately 10% of women of reproductive age and exhibits tumor-like characteristics such as invasion, recurrence, and hormone-dependent proliferation despite its benign nature. Its pathogenesis is thought to involve hormonal imbalance, oxidative stress, hypoxia, immune dysregulation, and epigenetic alterations. This review summarizes how these factors contribute to lesion formation through intracellular signaling pathways, with a particular focus on the role of the stress-responsive transcription factor Forkhead box O (FOXO1). Methods: A comprehensive literature search was conducted using PubMed and Google Scholar without temporal restriction. Results: FOXO1 is a transcription factor that integratively regulates decidualization, cellular senescence, autophagy, and apoptosis. In the normal endometrium, under mild stress or hormonal stimulation, FOXO1 induces decidualization-associated genes (PRL, IGFBP1) and antioxidant enzymes, thereby promoting differentiation and survival. In contrast, in endometriosis, activation of the PI3K/AKT signaling pathway and an estrogen-dominant environment suppress the nuclear activity of FOXO1, leading to apoptosis resistance, accumulation of senescent cells, and chronic inflammation through the senescence-associated secretory phenotype (SASP). Moreover, depending on the intensity and duration of oxidative, metabolic, and environmental stress, FOXO1 drives distinct cellular fates—including decidualization, senescence, and apoptosis—thus contributing to the persistence and progression of endometriotic lesions. Conclusion: Dysregulation of the FOXO1-dependent cellular fate–control network plays a central role in the development of endometriosis. Elucidating the molecular mechanisms governing FOXO1 activity and its nuclear dynamics will be crucial for a comprehensive understanding of disease progression and for the development of novel therapeutic strategies. Full article

Objective: Identifying biomarkers that predict metastatic potential or guide treatment selection is critical for improving breast cancer (BC) management. Previously, we established the Mitotic Network Activity Index (MNAI) as a prognostic marker in BC. Here, we bioinformatically and experimentally evaluated MNAI as a biomarker for metastasis risk and therapeutic response. Methods: We used Kaplan–Meier and Cox proportional hazard regression analyses to assess the association between MNAI and distant metastasis-free survival (DMFS) across 14 published BC datasets. A total of 16 publicly available clinical trial datasets, including the I-SPY trials, were used to evaluate the predictive value of MNAI for treatment response. Additionally, wound-healing and transmembrane assays were conducted to determine the effects of PLK1, CHEK1, and BUB1 inhibition on BC cell migration and invasion. Results: High MNAI levels were strongly associated with shorter DMFS. Multivariate analysis further confirmed MNAI as an independent risk factor for DMFS, beyond estrogen receptor status and PAM50-based molecular subtypes. Functionally, pharmacologic disruption of the mitotic network using PLK1, CHEK1, or BUB1 inhibitors significantly reduced cell migration and invasion in MDA-MB-231 and BT-549 BC cell lines. Moreover, BC cells with high MNAI increased sensitivity to microtubule-targeting agents such as docetaxel, paclitaxel, and ixabepilone but increased resistance to tamoxifen, AKT1/2 inhibitors, and mTOR inhibitors. Consistent with these findings, analysis of 16 clinical trial cohorts revealed that patients with high MNAI achieved higher pathological complete response rates to taxane-containing and ixabepilone-based therapies. Conclusions: Our findings demonstrate the MNAI as a clinically actionable biomarker that can refine risk stratification and guide the selection of targeted or chemotherapy regimens, advancing precision medicine in BC management. Full article

Breast cancer remains the most frequently diagnosed malignant tumor among women worldwide, and the limited selectivity as well as the emerging resistance to currently used therapies highlight the need to search for new therapeutic compounds. Aromatase, a key enzyme in the estrogen biosynthesis pathway, represents a recognized molecular target in the treatment of hormone-dependent cancers. In this study, six new 1,3,4-thiadiazole derivatives containing two halogen-substituted aromatic rings were designed and synthesized as potential nonsteroidal aromatase inhibitors. The cytotoxic activity of the obtained compounds was evaluated against two breast cancer cell lines: MCF-7 (estrogen-dependent) and MDA-MB-231 (estrogen-independent). All tested compounds exhibited concentration-dependent cytotoxic activity against MCF-7 cells, with the strongest effects observed for compounds A2, A3, B1, and B3 (IC₅₀ ≈ 52–55 µM). In contrast, none of the tested compounds showed significant activity against MDA-MB-231 cells (IC₅₀ > 100 µM), suggesting their selectivity toward estrogen-dependent cancer cells. Compound B3, identified as the most promising, was further subjected to in silico analyses. Molecular docking and molecular dynamics simulations revealed that B3 occupies a binding site similar to that of the co-crystallized native inhibitor and forms interactions characteristic of strong aromatase inhibitors. The obtained results confirm a mechanism of action related to aromatase inhibition and indicate that fluorophenyl-substituted 1,3,4-thiadiazole derivatives represent a promising scaffold for the design of new, selective, and less toxic aromatase inhibitors. Full article

Obesity and menopausal hypoestrogenism interact in a way that worsens insulin resistance and increases the risk of metabolic diseases. This study evaluated the effects of a diet composed of liquid chickpea sprouts (CS) on these problems. Sixty-four female Wistar rats were assigned to four experimental groups: a control group (Ctrl); a hypoestrogenic (HE) group, induced by ovariotomy; an obese (Ob) group, fed a high-sucrose diet; and a hypoestrogenic-obese (HE-Ob) group. Each group was subdivided into animals treated with chickpea sprouts (CS, 0.9 g/kg/day) or with a vehicle for four weeks. The results showed that CS significantly improved glucose tolerance and restored insulin sensitivity, normalizing the HOMA-IR index in both the Ob and HE-Ob groups. In addition, CS reduced serum triglycerides, reversed hepatic steatosis, and caused a favorable redistribution of adipose tissue, leading to decreased mesenteric fat accumulation. In conclusion, chickpea sprouts have protective metabolic effects by improving glucose homeostasis, reducing blood lipids, and mitigating liver damage in an estrogen-deficient model of obesity. These findings support the potential of chickpea sprouts as a dietary intervention to help prevent metabolic complications in obese postmenopausal women. Full article

Background and Clinical Significance: Up to 30% of patients with HR+/HER2-early breast cancer (eBC) may experience distant recurrence, and patients with high-risk clinical features have a higher likelihood of recurrence. For these patients, the addition of a CDK4/6 inhibitor to standard adjuvant endocrine therapy (ET) has demonstrated a significant reduction in the risk of invasive and distant recurrence. Despite that, a small subset of patients still experience distant relapse. To date, the characteristics of patients who relapse on adjuvant CDK 4/6i are not well defined. Case Presentation: Here we report the case of a patient with early-stage HR+/HER2− breast cancer at high risk of recurrence, who experienced distant metastatic relapse during adjuvant therapy with abemaciclib plus ET, with a shift in the tumor subtype to triple-negative. Genomic alterations associated with ET and cyclin-dependent kinase 4 and 6 inhibitor resistance were analyzed with next-generation sequencing (NGS) carried out at recurrence. Results showed P53 and PI3KCA pathway alterations, but no ESR1 mutation or RB1 mutations. The duration was 12 months for adjuvant abemaciclib, and the first-line metastatic treatment lasted less than 3 months. Conversely, T-DXd administered due to the presence of HER2-low showed excellent effectiveness. Conclusions: The management of breast cancer relapse occurring during adjuvant therapy with CDK4/6 inhibitors is challenging. Performing a re-biopsy is crucial due to the possible loss of estrogen receptors, which would require a change in therapeutic strategy no longer based on endocrine therapy. In cases that remain luminal, knowledge of the mutational profile may help to offer patients novel targeted treatments. Full article

Background/Objectives: Therapeutic resistance remains a major obstacle in breast cancer management, particularly among estrogen receptor-positive (ERα⁺) tumors that initially respond to endocrine therapy such as tamoxifen. Type XI collagen (COL11A1), a minor fibrillar collagen secreted by cancer-associated fibroblasts, has recently emerged as a stromal biomarker linked to tumor progression, immune modulation, and poor prognosis in several solid malignancies. Methods: We conducted a narrative review of the literature indexed in PubMed, Scopus, and Web of Science between 2011 and 2025, including original research, reviews, and clinical studies addressing COL11A1 expression and function in breast cancer. Mechanistic studies in other cancer types (ovarian, pancreatic, lung) were also evaluated when relevant to breast cancer biology. Results: Across multiple cancer types, COL11A1 overexpression correlates with stromal remodeling, epithelial–mesenchymal transition, and resistance to both hormone therapy and chemotherapy. In breast cancer, emerging data suggest a potential prognostic role and possible involvement in shaping the immune microenvironment. Nevertheless, most evidence derives from retrospective or preclinical studies, and clinical validation remains limited. Conclusions: COL11A1 represents a promising, though still exploratory, biomarker of therapeutic resistance and immune modulation in breast cancer. Future prospective and subtype-specific studies are needed to clarify its diagnostic and therapeutic value and to determine whether its inclusion in immunohistochemical panels could enhance patient stratification and guide personalized treatment. Full article