Breast cancer poses a substantial health challenge for the world’s over-70 population. However, data on the impact and epidemiology of breast cancer in this age group are limited. We aimed to evaluate global, regional, and national breast cancer trends among those aged 70 and older between 1990 and 2021. In this trend analysis based on the 2021 Global Burden of Diseases (GBD), we report on the incidence rates and Global Burden of Diseases (GBD) disability-adjusted life years (DALYs) counts, as well as the incidence rates per 100,000 individuals and average annual percentage changes (AAPCs) for breast cancer among individuals aged 70 and above at the global, regional, and national levels. We analyzed these global trends by age, sex, and socio-developmental index (SDI). Joinpoint regression elucidates pivotal trend shifts. From 1990 to 2021, the global incidence of breast cancer in the over-70 population modestly increased from 104 to 107 per 100,000, with significant trend changes in 1995, 2005, and 2018. Regionally, High-income North America had the highest incidence in 2021, while North Africa and the Middle East saw the steepest rise in incidence and DALYs. The only decrease was in the High SDI quintile. The 70–74 age group experienced the largest increase globally, with rates rising from 86.3 to 90 per 100,000 (AAPC 0.27). From 1990 to 2021, global breast cancer incidence in the over-70 population saw a slight uptick, contrasted by a significant reduction in DALYs, likely due to progress in endocrine and targeted therapies. This underscores the critical need for enhanced screening and personalized treatments for older patients.

Background: Studies have shown that there is a connection between estrogen receptor (ER) and glucocorticoid receptor (GR), which can impact the epithelial-mesenchymal transition (EMT) process and contribute to endocrine resistance in breast cancer. However, the specific mechanism is unclear. It is crucial to investigate this mechanism further. Methods: This study aimed to confirm the role of GR in breast cancer endocrine resistance. Based on our hypothesis, GR is linked to a gene involved in the EMT process, and thus contributes to endocrine resistance in breast cancer. We obtained survival data and GR expression data from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). Additionally, we gathered GR expression data from Gene Expression Omnibus (GEO). Using Cytoscape, we constructed a protein-protein interaction (PPI) network and identified key genes. Data of Vimentin, E-cad, and Wnt/β-catenin expression were obtained from The Cancer Genome Atlas (TCGA). We used the co-expression method to identify key proteins. UALCAN and cBioPortal were utilized to verify the function of the key protein. Results: In ER+ breast cancer, GR (P=3.12780899271121E−08) and zinc finger E-box binding homeobox 1 (ZEB1) (P=1.716157E−01) were lowly expressed and down-regulated genes of GR differentially expressed genes were enriched in cell adhesion molecules. We screened for the key protein ZEB1 and found high levels of it was positively associated with prolonged recurrence-free survival (RFS) in patients receiving endocrine therapy (P=0.0024), while high levels of E-cad were negatively associated (P=0.0038). GR expression was positively associated with ZEB1 (Spearman =0.29, P=8.50e−21), negatively associated with E-cad (Spearman =−0.13, P=5.17e−5), and negatively associated with the SETD1B (Spearman =−0.14, P=1.527e−5), a gene downstream of ZEB1. In contrast, ZEB1 expression was negatively correlated with E-cad (Spearman =−0.081, P=3.132e−3) and negatively correlated with SET domain-containing 1B (SETD1B) (Spearman =−0.177, P=9.07e−11). Conclusions: In ER+ breast cancers, GR expression is suppressed, and the EMT process is inhibited by suppressing ZEB1 expression and thus promoting E-cad expression. For the investigation of endocrine medication resistance in breast cancer, it is crucial to identify the mechanisms by how GR participates in the EMT process.

Triple‐negative breast cancer (TNBC) remains poorly responsive to immunotherapy, and how ferroptosis can be leveraged to enhance antitumor immunity is unclear. Here, we identify the mitochondrial aspartate/glutamate carrier SLC25A13 as a key immunometabolic driver in TNBC. SLC25A13 is upregulated in breast cancer, predicts poor prognosis, and is associated with reduced CD8 ⁺ T‐cell infiltration. Functionally, SLC25A13 promotes tumor growth, migration, and metastasis while suppressing ferroptosis and weakening CD8 ⁺ T‐cell‐mediated cytotoxicity. Mechanistically, SLC25A13 interacts with STAT3, enhances complex I‐linked oxidative phosphorylation, restrains mitochondrial ROS, and promotes STAT3 activation and nuclear translocation. Nuclear STAT3 directly induces IFI6, which preserves mitochondrial function, limits lipid peroxidation and Fe ^{2 +} accumulation, and thereby confers ferroptosis resistance and immune evasion. Through structure‐guided screening, we identified HY‐QS02682823 as a small‐molecule degrader of SLC25A13 that triggers lysosome‐dependent SLC25A13 loss, enhances ferroptosis, restores CD8 ⁺ T‐cell effector function, and improves the efficacy of anti‐PD‐1 therapy in syngeneic TNBC models. These findings identify the SLC25A13–STAT3–IFI6 axis as a key regulator of ferroptosis resistance and immune evasion in TNBC.

Breast cancer is the most common malignancy in women and a major cause of cancer-related mortality. While early-stage disease is often curable, many patients ultimately develop distant metastases, with the brain representing one of the most devastating sites. Breast cancer brain metastasis (BCBM) is particularly prevalent in human epidermal growth factor receptor 2 (HER2)-positive and triple-negative subtypes, leading to severe neurological symptoms, diminished quality of life, and poor prognosis. Despite progress in systemic therapy for primary tumors, outcomes for patients with BCBM remain poor, and these patients are frequently excluded from clinical trials. The pathogenesis of BCBM involves complex interactions between tumor cells and the central nervous system microenvironment. Crossing the blood-brain barrier and adapting to the brain niche requires tumor-stroma crosstalk, including signaling with astrocytes and microglia, which promotes immune evasion, therapeutic resistance, and metastatic outgrowth. Although advances in preclinical models and molecular profiling have provided valuable insights, critical mechanisms remain incompletely understood. Systemic therapies are increasingly important, with HER2-targeted agents, tyrosine kinase inhibitors, and subtype-specific regimens showing activity. Novel approaches, including poly (ADP-ribose) polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidylinositol 3-kinase inhibitors, and antibody-drug conjugates, are under evaluation. This review synthesizes epidemiology, molecular mechanisms, and emerging therapies of BCBM, underscoring advances achieved and highlighting the urgent need for novel targeted strategies and inclusive clinical trials.

The tumor microenvironment (TME) is now understood as an active regulator of therapeutic vulnerability. In this Review, we use an integrative stromal-checkpoint framework, informed by published stromal and fibroblast checkpoint studies, to describe stromal programs that couple extracellular matrix (ECM) remodeling, metabolic stress, vascular dysfunction, and immune exclusion into treatment-resistant tumor ecologies. We focus on a disintegrin and metalloproteinase 12 (ADAM12) because ADAM12-high or ADAM12-positive tumor-stromal states have been linked to collagen-rich desmoplasia, mechanotransduction, hypoxia-associated stress, lactate-associated acidosis, immune-excluded spatial organization, and therapy resistance in solid tumors. Evidence spans fibroblast, mesenchymal stromal-cell, and tumor-cell perturbation studies; mechanistic substrate and signaling analyses; spatial and clinical datasets; and broader tissue-level immune contexts relevant to lymphatic drainage, tumor-draining lymph node (TDLN) priming, tissue-resident immune cells, and ILC2/type 2 immune programs. Across these evidence layers, ADAM12 emerges as an isoform-aware and cell-of-origin-dependent marker, amplifier, and context-dependent candidate target for selected high-barrier tumor states. We discuss how ADAM12-informed biomarkers, spatial barrier profiling, and stromal-priming strategies can support patient stratification and combination-therapy design. Overall, ADAM12-associated biology provides a useful model for examining how stromal resistance may be built, maintained, and therapeutically remodeled in selected tumor contexts.