Search Results (940)

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R² = 0.86; Q²_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC₅₀ > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential. Full article

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In this study, tumor specimens from 104 TNBC patients were analyzed to characterize molecular and clinicopathological features and to assess the expression and therapeutic potential of four key surface markers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), tissue factor (TF), and trophoblast cell surface antigen (TROP2). Multiplex immunofluorescence (mIF) demonstrated elevated EGFR and TROP2 expression in the majority of samples. Significant positive correlations were observed between EGFR and TF, as well as between TROP2 and both TF and EpCAM. Expression analyses revealed increased EGFR and TF levels with advancing tumor stage, whereas EpCAM expression declined in advanced-stage tumors. TROP2 and TF expression were significantly elevated in higher-grade tumors. Additionally, EGFR and EpCAM levels were significantly higher in patients with elevated Ki-67 indices. Binding specificity assays using single-chain variable fragment (scFv-SNAP) fusion proteins confirmed robust targeting efficacy, particularly for EGFR and TROP2. These findings underscore the therapeutic relevance of EGFR and TROP2 as potential biomarkers and targets in TNBC. Full article

Background/Objectives: Gastrin-releasing peptide receptor (GRPR) is overexpressed in breast cancer and might be used as a theranostics target. The expression of GRPR strongly correlates with estrogen receptor (ER) expression. Visualization of GRPR-expressing breast tumors might help to select the optimal treatment. Developing GRPR-specific probes for SPECT would permit imaging-guided therapy in regions with restricted access to PET facilities. In this first-in-human study, we evaluated the safety, biodistribution, and dosimetry of the [^99mTc]Tc-DB8 GRPR-antagonistic peptide. We also addressed the important issue of finding the optimal injected peptide mass. Methods: Fifteen female patients with ER-positive primary breast cancer were enrolled and divided into three cohorts receiving [^99mTc]Tc-DB8 (corresponding to three distinct doses of 40, 80, or 120 µg DB8) comprising five patients each. Additionally, four patients with ER-negative primary tumors were injected with 80 µg [^99mTc]Tc-DB8. The injected activity was 360 ± 70 MBq. Planar scintigraphy was performed after 2, 4, 6, and 24 h, and SPECT/CT scans followed planar imaging 2, 4, and 6 h after injection. Results: No adverse events were associated with [^99mTc]Tc-DB8 injections. The effective dose was 0.009–0.014 mSv/MBq. Primary tumors and all known lymph node metastases were visualized irrespective of injected peptide mass. The highest uptake in the ER-positive tumors was 2 h after injection of [^99mTc]Tc-DB8 at a 80 µg DB8 dose (SUV_max 5.3 ± 1.2). Injection of [^99mTc]Tc-DB8 with 80 µg DB8 provided significantly (p < 0.01) higher uptake in primary ER-positive breast cancer lesions than injection with 40 µg DB8 (SUV_max 2.0 ± 0.3) or 120 µg (SUV_max 3.2 ± 1.4). Tumor-to-contralateral breast ratio after injection of 80 μg was also significantly (p < 0.01, ANOVA test) higher than ratios after injection of other peptide masses. The uptake in ER-negative lesions was significantly lower (SUV_max 2.0 ± 0.3) than in ER-positive tumors. Conclusions: Imaging using [^99mTc]Tc-DB8 is safe, tolerable, and associated with low absorbed doses. The tumor uptake is dependent on the injected peptide mass. The injection of an optimal mass (80 µg) provides the highest uptake in ER-positive tumors. At optimal dosing, the uptake was significantly higher in ER-positive than in ER-negative lesions. Full article

Drug resistance remains a critical barrier to effective treatment in several cancers, particularly triple-negative breast cancer (TNBC). Estrogen receptor α36 (ERα36), a variant of the estrogen receptor in ER-negative breast cancer cells, plays important roles in cancer cell proliferation. We investigated the role of ERα36 in regulating multidrug resistance protein 1 (MDR1) in MDA-MB-231 human breast cancer cells. The activation of ERα36 by BSA-conjugated estradiol (BSA-E2) increased cell viability under Adriamycin exposure, suggesting its involvement in promoting drug resistance. BSA-E2 treatment significantly reduced the intracellular rhodamine-123 levels by activating the MDR1 efflux function, which was linked to increased MDR1 transcription and protein expression. The mechanical ERα36-mediated BSA-E2-induced activation of EGFR and downstream signaling via c-Src led to an activation of the Akt/ERK pathways and transcription factors, NF-κB and CREB. Additionally, ERα36 is involved in activating Wnt/β-catenin pathways to induce MDR1 expression. The silencing of ERα36 inhibited the BSA-E2-induced phosphorylation of Akt and ERK, thereby reducing MDR1 expression via downregulation of NF-κB and CREB as well as Wnt/β-catenin signaling. These findings demonstrated that ERα36 promotes MDR1 expression through multiple non-genomic signaling cascades, including Akt/ERK-NF-κB/CREB and Wnt/β-catenin pathways, and highlight the role of ERα36 as a promising target to enhance chemotherapeutic efficacy in TNBC. Full article

Background: Gastric cancer (GC) is a highly heterogeneous disease and remains one of the major causes of cancer-related mortality worldwide. The vast majority of GC cases are adenocarcinomas including diffuse and intestinal GC that may differ in their incidence between Asian and non-Asian cohorts. The intestinal-subtype GC has declined over the past 50 years. In contrast to the intestinal-subtype adenocarcinoma, the incidence of diffuse-subtype GC, often associated with poor overall survival, has constantly increased in the USA and Europe. The aim of this study was to analyze the expression and clinical significance of steroid hormone receptors, two membrane-bound receptors (ERRγ and GPER), and several genes involved in epigenetic alterations. The findings may contribute to revealing events driving tumorigenesis and may aid prognosis. Methods: Using mRNA from diffuse and intestinal GC tumor samples, the expression level of 11 genes, including those coding for sex hormone receptors (estrogen receptors ERα and ERβ), progesterone receptor (PR) and androgen receptor (AR), and the putative relevant ERRγ and GPER receptor were determined by RT-qPCR. Results: In diffuse GC, the expression of ERα, ERβ, PR and AR differed from their expression in the intestinal subtype. The expression of ERα and ERβ was strongly increased in the diffuse subtype compared to the intestinal subtype (×1.90, p = 0.001 and ×2.68, p = 0.002, respectively). Overexpression of ERα and ERβ was observed in diffuse GC (15 and 42%, respectively). The expression levels of PR and AR were strongly decreased in the intestinal subtype as compared to diffuse GC (×0.48, p = 0.005 and ×0.25, p = 0.003, respectively; 37.5% and 56% underexpression). ERα, ERβ, PR and AR showed notable differences for clinicopathological correlation in the diffuse and intestinal GC. A significant decrease of ERα, ERβ, PR and AR in intestinal GC correlated with the absence of lymphatic invasion and lower TNM (I-II). In diffuse GC, among the hormone receptors, increases of ERs and PR mainly correlated with expression of growth factors and receptors (IGF1, FGF7 and FGFR1), and with genes involved in epithelial-mesenchymal transition (VIM and ZEB2) or cell migration (MMP2). Our results also report the strong decreased expression of ERRγ and GPER (two receptors that bind estrogen or xenoestrogens) in diffuse and intestinal subtypes. Conclusions: Our study identified new target genes, namely hormone receptors and membrane receptors (ERRγ and GPER), whose expression is associated with an aggressive phenotype of diffuse GC, and revealed the importance of epigenetic factors (EZH2, HOTAIR, H19 and DNMT1) in gastric cancers. Full article

Estrogens regulate many physiological processes in the human body, including the cardiovascular system. Importantly, Estradiol (E2) exerts its vascular protective actions, in part, by promoting endothelial repair via induction of endothelial cell (EC) proliferation, migration and angiogenesis. Recent evidence that microRNAs (miRNAs) play an important role in vascular health and disease as well as in regulating Estrogen actions in many cell types. We hypothesize that E2 may mediate its vascular protective actions via the regulation of miRNAs. Following initial screening, we found that E2 downregulates the levels of miR-193a-3p in ECs. Moreover, miR-193a-3p downregulation by miR-193a-3p-antimir mimicked the effects as E2 on EC growth, migration, and capillary formation. Restoring miR-193a-3p levels with mimics after E2 treatment abrogated the vasculogenic actions of E2, suggesting a key role of miR-193a-3p in E2-mediated EC-growth-promoting effects. We further investigated the cellular mechanisms involved and found that miR-193a-3p inhibits angiogenesis by blocking phosphoinositide-3-kinase (PI3K)/Akt-vascular endothelial growth factor (VEGF) and Activin receptor-like kinase 1 (ALK1)/SMAD1/5/8 signaling in ECs, both pathways that are important in E2-mediated vascular protection. Additionally, using reverse transcription polymerase chain reaction (RT-PCR), we demonstrate that E2 downregulates miR-193a-3p in ECs via Estrogen Receptor (ER)α, but not ERβ or G protein-coupled estrogen receptor (GPER). Moreover, these actions occur post-transcriptionally, as the expression of pri-miR-193a-3p was not affected. The anti-angiogenic actions of miR-193a-3p were also observed in in vivo Matrigel implant-based capillary formation studies in ovariectomized mice where E2 induced capillary formation, and these effects were abrogated in the presence of miR-193a-3p, but not in the control mimic. Assessment of miR-193a-3p levels in plasma collected from in vitro fertilization (IVF) subjects with low and high E2 levels showed significantly lower miR-193a-3p levels in responders during the high E2 period. Hence, our findings provide the first evidence that miR-193a-3p mimic inhibits angiogenesis whereas its antimir is angiogenic. Importantly, E2 mediates its regenerative actions on ECs/capillary formation by downregulating endogenous miR-193a-3p expression. Both miR-193a-3p mimic or antimir may represent important therapeutic molecules to prevent or to induce endothelial function in treating pathophysiologies associated with capillary growth. Full article

The abnormal growth of smooth muscle cells (SMCs) contributes to the vascular remodeling associated with coronary artery disease, a leading cause of death in women. Estradiol (E2) mediates cardiovascular protective actions, in part, by inhibiting the abnormal growth (proliferation and migration) of SMCs through various mechanism. Since microRNAs (miRNAs) play a major role in regulating cell growth and vascular remodeling, we hypothesize that miRNAs may mediate the protective actions of E2. Following preliminary leads from E2-regulated miRNAs, we found that platelet-derived growth factor (PDGF)-BB-induced miR-193a in SMCs is downregulated by E2 via estrogen receptor (ER)α, but not the ERβ or G-protein-coupled estrogen receptor (GPER). Importantly, miR-193a is actively involved in regulating SMC functions. The ectopic expression of miR-193a induced vascular SMC proliferation and migration, while its suppression with antimir abrogated PDGF-BB-induced growth, effects that were similar to E2. Importantly, the restoration of miR-193a abrogated the anti-mitogenic actions of E2 on PDGF-BB-induced growth, suggesting a key role of miR-193a in mediating the growth inhibitory actions of E2 in vascular SMCs. E2-abrogated PDGF-BB, but not miR-193a, induced SMC growth, suggesting that E2 blocks the PDGF-BB-induced miR-193a formation to mediate its anti-mitogenic actions. Interestingly, the PDGF-BB-induced miR-193a formation in SMCs was also abrogated by 2-methoxyestradiol (2ME), an endogenous E2 metabolite that inhibits SMC growth via an ER-independent mechanism. Furthermore, we found that miR-193a induces SMC growth by activating the phosphatidylinositol 3-kinases (PI3K)/Akt signaling pathway and promoting the G1 to S phase progression of the cell cycle, by inducing Cyclin D1, Cyclin Dependent Kinase 4 (CDK4), Cyclin E, and proliferating-cell-nuclear-antigen (PCNA) expression and Retinoblastoma-protein (RB) phosphorylation. Importantly, in mice, treatment with miR-193a antimir, but not its control, prevented cuff-induced vascular remodeling and significantly reducing the vessel-wall-to-lumen ratio in animal models. Taken together, our findings provide the first evidence that miR-193a promotes SMC proliferation and migration and may play a key role in PDGF-BB-induced vascular remodeling/occlusion. Importantly, E2 prevents PDGF-BB-induced SMC growth by downregulating miR-193a formation in SMCs. Since, miR-193a antimir prevents SMC growth as well as cuff-induced vascular remodeling, it may represent a promising therapeutic molecule against cardiovascular disease. Full article

The effects of a methanol extract of Nymphaea odorata (MeNO) rhizomes, its fractions and the active compound (methyl gallate, MeG) were investigated in estrogen receptor-positive (ER+) breast cancer cell lines MCF-7 and T47-D:A18, as well as ER-negative line SKBr3. Cell viability and cytotoxicity were determined using CellTiter-Glo^® 2.0 assays at concentrations ranging from 1 to 100 μg/mL. Caspase activity and apoptosis were determined using Caspase-Glo^® 3/7, Caspase-Glo^® 8, and ApoTox-Glo™ triplex assays, as well as qPCR. Total RNA was isolated from MCF-7 cells treated with MeG. RNA-seq libraries were prepared using a Universal Plus mRNASeq kit, and sequencing was performed on a NovaSeq 6000. MeNO inhibited the growth of MCF-7 cells with an IC₅₀ of 14.1 μg/mL, as well as T47-D:A18 (IC₅₀ of 25.6 μg/mL) and SKBr3 cells (IC₅₀ of 35.5 μg/mL). Bioassay-guided fractionation of MeNO in MCF-7 cells identified the active fraction containing one compound, namely methyl gallate (MeG). MeG had an IC₅₀ of 8.6 μg/mL in MCF-7 cells. Transcriptomic analysis of MeG-treated MCF-7 cells showed differential expression of 10,634 genes, with 5643 upregulated and 4991 downregulated (FDR < 0.05). Ingenuity pathway analysis revealed the involvement of 43 canonical pathways, with the top upregulated pathways including apoptosis, autophagy, and the unfolded protein response pathways. Full article

Background/Objectives: HIF-1α and ERRα are both implicated in breast cancer progression, yet their functional interplay remains poorly understood. This study investigates their molecular crosstalk in the context of hypoxia-induced drug resistance. Methods: MCF-7 (estrogen receptor, ER-positive) spheroids and CoCl₂-treated SK-BR-3 (ER-negative) cells were used to model tumor hypoxia. Protein expression, coimmunoprecipitation, chromatin immunoprecipitation (ChIP), pharmacological inhibition, and siRNA-mediated gene silencing were employed to assess physical and functional interactions. Immunohistochemistry (IHC) on a tissue microarray (TMA) of 168 invasive breast carcinomas was performed to evaluate clinical relevance. Results: ERRα levels remained unchanged under hypoxia, while its coactivator, Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1 α (PGC-1α), was upregulated. ERRα physically interacted with HIF-1α and was required for HIF-1 transcriptional activity under hypoxic conditions. ChIP assays showed that ERRα-driven overexpression of Permeability glycoprotein 1 (P-gp) and Vascular Endothelial Growth Factor (VEGF) was mediated by HIF-1α binding to the MDR1 and VEGF promoters. Inhibition or silencing of ERRα reversed P-gp overexpression and restored intracellular doxorubicin. TMA analysis confirmed the clinical correlation between ERRα, HIF-1α, and P-gp expression, highlighting the role of ERRα in hypoxia-induced drug resistance. ERRα expression was independent of ER status, suggesting an estrogen-independent function. Conclusions: This study identifies a novel physical and functional interaction between ERRα and HIF-1α that promotes chemoresistance in hypoxic breast tumors. Targeting ERRα may represent a promising therapeutic strategy to overcome drug resistance in aggressive, ER-independent breast cancer subtypes. Full article

Background: Male breast cancer (MBC) is extremely rare, representing less than 1% of breast cancer (BC). Owing to the rarity, there is a substantial knowledge gap regarding the survival trends of MBC compared with female breast cancer (FBC). Methods: We queried the National Cancer Database for BC patients diagnosed during 2004–2018 and utilized an inverse propensity weighted cox regression model assessed the association between sex and overall survival (OS) and survival trends over time by sex. Results: We identified 24,055 MBC and 2,532,470 FBC patients. Patients with MBC were older (mean age: 65.6 vs. 61.4 years), and more likely to have stage IV at diagnosis (7% vs. 4.7%), larger tumors (cT4: 6% vs. 3.7%), and node-positive disease (18.5% vs. 15.5%) (p < 0.001) compared with FBC. MBC were more likely to be estrogen (ER) (88.5% vs. 78.5%) and progesterone receptor (PR) (79.6% vs. 68%) positive and less likely to be HER2 receptor positive (7.9% vs. 9.3%) or triple negative (2.8% vs. 7.6%) compared with FBC (all p < 0.001). The OS rates were lower in MBC compared with FBC (5-year: 73% vs. 83%; 10-year: 54% vs. 70%, p < 0.001). In the propensity weighted cox-regression model, males had higher mortality than females with BC (HR 2.8, 95% CI 2.88–2.9, p < 0.001). The 5-year OS rates increased steadily for FBC from 2004–2015; however, the survival rates did not improve for MBC over the last decade. Conclusions: Our study shows that MBC patients continue to have poor OS compared with patients with FBC and no significant improvement in survival of MBC patients over the past decade. These results underscore the need to investigate personalized treatment interventions for patients with MBC to improve outcomes. Full article

Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality worldwide, with increasing evidence suggesting that their origins may lie in prenatal life. Endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), have been implicated in the alteration of fetal programming mechanisms that cause a predisposition to long-term cardiovascular vulnerability. However, the impact of prenatal endocrine disruption on fetal heart development and its sex-specific nature remains incompletely understood. This study investigates the molecular and structural effects of low-dose prenatal BPA exposure on fetal rat hearts. Our results reveal that BPA disrupts estrogen receptor (ER) signaling in a sex-dependent manner, with distinct alterations in ERα, ERβ, and GPER expression. BPA exposure also triggers significant inflammation, oxidative stress, and ferroptosis; this is evidenced by elevated NF-κB, IL-1β, TNF-α, and NLRP3 inflammasome activation, as well as impaired antioxidant defenses (SOD1, SOD2, CAT, and SELENOT), increased lipid peroxidation (MDA) and protein oxidation, decreased GPX4, and increased ACSL4 levels. These alterations are accompanied by increased markers of cardiac distension (ANP, BNP), extracellular matrix remodeling mediators, and pro-fibrotic regulators (Col1A1, Col3A1, TGF-β, and CTGF), with a more pronounced response in males. Histological analyses corroborated these molecular findings, revealing structural alterations as well as glycogen depletion in male fetal hearts, consistent with altered cardiac morphogenesis and metabolic stress. These effects were milder in females, reinforcing the notion of sex-specific vulnerability. Moreover, prenatal BPA exposure affected myocardial fiber architecture and vascular remodeling in a sex-dependent manner, as evidenced by reduced expression of desmin alongside increased levels of CD34 and Ki67. Overall, our findings provide novel insights into the crucial role of prenatal endocrine disruption during fetal heart development and its contribution to the early origins of CVD, underscoring the urgent need for targeted preventive strategies and further research into the functional impact of BPA-induced alterations on postnatal cardiac function and long-term disease susceptibility. Full article

Long-chain fatty acids (LCFAs) have emerged as important regulators of cancer metabolism, but their impact on hormone receptor expression in breast cancer (BCA) remains poorly understood. In this study, we investigated the effects of five LCFAs—linoleic acid (LA), oleic acid (OA), elaidic acid (EA), palmitic acid (PA), and α-linolenic acid (LNA)—on two BCA cell lines: luminal-type MCF7 and triple-negative MDA-MB-231 (MB231). All LCFAs suppressed cell viability and mitochondrial function in a dose-dependent manner, accompanied by decreased membrane potential, increased reactive oxygen species production, and a metabolic shift. Notably, OA reduced both mRNA and nuclear protein levels of estrogen receptor alpha (ERα) in MCF7 cells, leading to impaired responses to estradiol and tamoxifen. In contrast, PA induced nuclear ERα expression in MB231 cells, although ER signaling remained inactive. MicroRNA profiling revealed that OA upregulated ER-suppressive miR-22 and miR-221 in MCF7, while PA increased miR-34a in MB231, contributing to ERα induction. These findings suggest that specific LCFAs modulate ER expression through epigenetic and post-transcriptional mechanisms, altering hormonal responsiveness in BCA. Our results offer new insights into how dietary lipids may influence therapeutic efficacy and tumor behavior by regulating nuclear receptor signaling. Full article

Background/Objectives: The effects of combining chemotherapy with hormonal therapy based on hormone receptor (HR) expression in epithelial ovarian, fallopian tube, or primary peritoneal (EOC) remain unclear. This study evaluated the efficacy and safety of physician-chosen chemotherapy combined with hormonal therapy in patients with heavily pretreated advanced EOC, stratified by HR expression. Methods: This phase II, multicenter, pilot study included patients with heavily pretreated advanced EOC, allocated to estrogen receptor (ER)-dominant or progesterone receptor (PR)-dominant arms. Patients in the ER-dominant arm received tamoxifen plus physician-selected chemotherapy, while those in the PR-dominant arm received megestrol acetate (MA) plus chemotherapy. The primary outcome was the best objective response rate (ORR) for six months, assessed using an optimal two-stage Simon design. Results: Among 33 ER-dominant patients with high-grade serous carcinoma (HGSC), the six-month best ORR was 27.3% (3% complete response, 24.2% partial response). The six-month ORR and clinical benefit rate (CBR) were 18.8% and 37.5%, respectively, with 62.5% experiencing progressive disease (PD). Among three PR-dominant patients (two clear cell carcinoma and one HGSC), the six-month best ORR was 0%. The six-month ORR and CBR were also 0%, and all experienced PD within six months. No unacceptable toxicity related to tamoxifen or MA was encountered. Conclusions: In heavily pretreated advanced HGSC patients with ER-dominant expression, chemotherapy combined with tamoxifen showed encouraging clinical activity with favorable safety. While limited by the study design, these findings suggest a potential role for tailored hormonal therapy combined with chemotherapy based on HR expression in heavily pretreated advanced EOC. Clinical Trial Registration: KCT0004571 Full article

Breast cancer is the leading threat to the health of women, with a rising global incidence linked to social and psychological factors. Among its subtypes, triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is highly heterogeneous with early metastasis and a poor prognosis, making it the most challenging subtype. Mounting evidence shows that the mitochondrial quality control (MQC) system is vital for maintaining cellular homeostasis. Dysfunction of the MQC is tied to tumor cell invasiveness, metastasis, and chemoresistance. This paper comprehensively reviews the molecular link between MQC and TNBC development. We focused on how abnormal MQC affects TNBC progression by influencing chemoresistance, immune evasion, metastasis, and cancer stemness. On the basis of current studies, new TNBC treatment strategies targeting key MQC nodes have been proposed. These findings increase the understanding of TNBC pathogenesis and offer a theoretical basis for overcoming treatment challenges, providing new research angles and intervention targets for effective precision therapy for TNBC. Full article

Background: Breast cancer is the most prevalent women’s cancer, representing about a third of all cancers diagnosed in women. Estrogen receptor (ER) is an important transcription factor expressed in 70% to 75% of all breast cancers. Of these breast cancers, the majority express ER robustly in 91–100% of tumor cells. However, a minority of breast cancers express ER in intermediate levels between 11% and 90% of tumor cells. The characteristics and outcomes of this intermediate subset of ER-positive breast cancers are not well studied. Methods: We retrospectively reviewed the medical records of all breast cancer patients treated in our Cancer Center over a period of 8 years. Patients were grouped according to the level of ER expression in tumors with negative/low ER expression, intermediate ER expression, and high ER expression, and the groups were compared for tumor characteristics and outcomes. Results: Patients with high ER levels (91% to 100%) represented 75.6% (600 of 794 patients), patients with intermediate ER expression represented 11.5% of the entire group (91 of 794 patients), and patients with negative/low ER expression (ER expression 0–10%) represented 12.9% of the entire cohort (103 of 794 patients). Patients with intermediate ER expression presented at a younger age than patients with high-ER cancers, as well as a more advanced stage and higher grade. These characteristics were more akin to patients with negative/low ER levels. Mastectomy was the surgical method of resection more commonly in ER-intermediate tumors than in ER-high tumors. The relapse-free survival (RFS) of patients with ER-intermediate cancers was worse than the RFS of patients that expressed ER robustly. Conclusion: The level of expression of ER defines groups of patients with varying characteristics and prognoses. Patients in the intermediate ER expression group had notable differences from patients in the high ER expression group including younger age, (more often) a higher grade, and low PR positivity. Differences observed between the group of patients with intermediate ER expression and that with high ER expression may help to prioritize therapeutic algorithms. Full article