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Breast cancer (BC) is a leading cause of cancer-related mortality in women worldwide, underscoring the need for novel therapeutic strategies. Focal adhesion kinase (FAK) has emerged as a promising oncological target due to its central role in tumor progression. Bruceine D (BD), a natural compound from Brucea javanica , exhibits anti-cancer properties, but its mechanism in BC via FAK inhibition remains unclear. We conducted a comprehensive investigation using BC cell lines. Cell viability and migration were assessed by MTT and transwell assays, respectively. The tube formation assay examines the effect of BD on angiogenesis. Mitochondrial function was evaluated by measuring reactive oxygen species (ROS), ATP production, and mitochondrial membrane potential (ΔΨm). Apoptosis was quantified via flow cytometry. RNA sequencing (RNA-seq) with pathway enrichment analysis was employed to identify FAK-associated signaling pathways, and key protein expression changes, including FAK and downstream factors, were validated by western blotting. BD significantly suppressed BC cell proliferation, migration, and angiogenesis by inducing mitochondrial dysfunction, characterized by elevated ROS levels, depleted ATP, and loss of ΔΨm. Clinical analysis confirmed FAK overexpression in BC tissues. Mechanistically, BD inhibited FAK signaling. RNA-seq further revealed that FAK inhibition modulated several downstream pathways, including the expression of LRG1, collectively leading to the induction of apoptosis. This study identifies BD as a potent small-molecule FAK inhibitor. Our findings delineate a FAK-centered mechanism of action for BD, supporting its further development as a promising therapeutic agent for BC.

Emerging evidences exposed that long noncoding RNAs (lncRNAs) play important roles in various tumor progression including breast cancer (BC). However, the role of IncRNA ADP-dependent glucokinase antisense RNA 1 (ADPGK-AS1) in BC progression remains undiscovered. Hence, this study aimed to investigate the role of ADPGK-AS1 in BC. qRT-PCR was performed to investigate ADPGK-AS1 expression level in BC tissues and cell lines. The effect of ADPGK-AS1 knockdown on BC cellular process was assessed by loss-of-function assay. Luciferase reporter and RIP assay were performed to investigate the combination between ADPGK-AS1 and miR-3196. The combination between miR-3196 and orthodenticle homeobox 1 (OTX1) was verified by luciferase reporter assay. Finally, rescue assays were performed to confirm the effects of ADPGK-AS1/miR-3196/OTX1 axis on BC development. ADPGK-AS1 expression level was upregulated in BC tissues and cell lines. High expression of ADPGK-AS1 predicted poor prognosis for BC patients. Functionally, ADPGK-AS1 promoted cell proliferation, migration, induced epithelial-mesenchymal transition (EMT) process, and suppressed cell apoptosis. Mechanistically, ADPGK-AS1 acted as a miR-3196 sponge to release OTX1 in BC cells. Currently, ADPGK-AS1 acted as a competing endogenous RNA (ceRNA) via modulating miR-3196/OTX1 axis in BC.

This study used a Mendelian randomization (MR) approach to investigate the causal relationship between genetically predicted endometriosis (EMS) and breast cancer risk. A total of 122,977 cases and 105,974 controls were included in the analysis, with gene-level summary data obtained from the Breast Cancer Association Consortium (BCAC). An inverse variance-weighting approach was applied to assess the causal relationship between EMS and breast cancer risk, and weighted median and MR-Egger regression methods were used to evaluate pleiotropy. Results showed a causal relationship between EMS and a decreased risk of overall breast cancer (odds ratio [OR] 0.95; 95% CI 0.90–0.99, p = 0.02). Furthermore, EMS was associated with a lower risk for estrogen receptor (ER)-positive breast cancer in a subgroup analysis based on immunohistochemistry type (OR 0.91; 95% CI 0.86–0.97, p = 0.005). However, there was no causal association between ER-negative breast cancer and survival (OR 1.00; 95% CI 0.94–1.06, p = 0.89). Pleiotropy was not observed. These findings provide evidence of a relationship between EMS and reduced breast cancer risk in invasive breast cancer overall and specific tissue types, and support the results of a previous observational study. Further research is needed to elucidate the mechanisms underlying this association.

Background This study aimed to construct, evaluate, and validate nomograms for breast cancer-specific survival (BCSS) and overall survival (OS) prediction in patients with HER2- overexpressing (HER2+) metastatic breast cancer (MBC). Methods The Surveillance, Epidemiology, and End Results (SEER) database was used to select female patients diagnosed with HER2 + MBC between 2010 and 2015. These patients were distributed into training and validation groups (7:3 ratio). Variables were screened using univariate and multivariate Cox regression analyses, and BCSS and OS nomograms were constructed to determine one-, three-, and five-year survival probabilities. The nomograms were evaluated and validated using the concordance index (C-index), time-dependent receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis. Stratification was evaluated using Kaplan–Meier curves and log-rank tests based on optimal total score cut-off values. We published web-based versions of these nomograms for clinical use. Results A total of 2,151 eligible patients were randomized into training ( n  = 1,505) and validation ( n  = 646) groups. Independent prognostic factors of BCSS and OS included: age; marital status; race; oestrogen receptor status; surgery; chemotherapy; and bone, brain, liver, and lung metastases. The C-indices for the BCSS and OS training groups were 0.707 and 0.702, respectively. The ROC, calibration, and decision curves demonstrated the strength of the nomograms. According to cut-off values, patients were categorized into low-, intermediate-, and high-risk groups, with significant differences in survival outcomes between them. Conclusion We constructed predictive nomograms and stratified risk to assess the prognosis of patients with HER2 + MBC, which could help inform therapeutic decisions. Trial registration Not applicable.

Introduction Breast cancer (BC) is a common malignant tumor affecting women across the world. LncRNAs are frequently implicated in the course of BC. The current study set out to determine the specific effect of lncRNA AGAP2-AS1 on BC cell resistance to apoptosis. Methods AGAP2-AS1 expression patterns in BC tissues and cells were evaluated. si-AGAP2-AS1 was transfected into MCF-7 cells, followed by the assessment of cell proliferation and apoptosis. In addition to detection of MTA1 expression patterns, the binding relation between AGAP2-AS1 and HuR was verified using RNA pull-down and RNA immunoprecipitation. Next, the regulation enrichment of AGAP2-AS1- and HuR to H3K27ac recruitment in the MTA1 promoter was analyzed. MCF-7 cell resistance to apoptosis was observed after the combined experiment of histone deacetylase inhibitor M344 and si-AGAP2-AS1. Lastly, xenografts tumors were established to detect tumor weight and volume, tumor apoptosis and growth as well as expression of AGAP2-AS1 and MTA1. Results AGAP2-AS1 was overexpressed in BC tissues and cells, and AGAP2-AS1 silencing inhibited cell proliferation but facilitated apoptosis. Physiologically, AGAP2-AS1 bound to HuR to stabilize its own expression, and AGAP2-AS1-HuR complex upregulated H3K27ac levels in the MTA1 promoter region to elevate MTA1 promoter activity and MTA1 expression. H3K27ac upregulation partially-annulled the promotive effect of si-AGAP2-AS1 on BC apoptosis by upregulating MTA1. si-AGAP2-AS1 in vivo inhibited MTA1 expression to enhance apoptosis and suppress tumor growth. Conclusion Collectively, our findings indicated that AGAP2-AS1 bound to HuR to stabilize its own expression, and AGAP2-AS1-HuR complex enhanced H3K27ac levels in the MTA1 promoter region to improve MTA1 promoter activity and MTA1 expression in BC cells, so as to augment BC cell resistance to apoptosis.

Purpose Increasing evidence has shown that the transcription factor SOX4 is closely associated with the development and progression of many malignant tumors. However, the effect of SOX4 on breast cancer is unclear. In this study, we purposed to investigate the role of SOX4 in the growth and metastasis in breast cancer and the underlying mechanism. Moreover, the effect of SOX4 on cancer cell resistance to chemotherapeutic agents was also evaluated in vitro and in vivo. Methods We used lentivirus technique to ectopically express SOX4 in MDA-MB-231 and SUM149 cells or knockdown SOX4 in BT474 cells, and examined the effect of these changes on various cellular functions. MTT assay was used to determine the cell viability as well as resistance to chemotherapeutic agents. The regulation of SOX4 on epithelial-mesenchymal transition (EMT)-related genes was analyzed using qRT-PCR. The binding of SOX4 to the CXCR7 gene was demonstrated using chromatin immunoprecipitation assay and dual-luciferase reporter activity assay. The effect of SOX4/CXCR7 axis on metastasis was examined using Transwell migration and Matrigel invasion assays. The expression of SOX4/CXCR7 in primary tumors and metastatic foci in lymph nodes was assessed using immunohistochemistry. Cellular morphology was investigated under phase contrast microscope and transmission electron microscopy. Moreover, the effect of SOX4 on tumor growth, metastasis, and resistance to chemotherapy was also studied in vivo by using bioluminescent imaging. Results SOX4 increased breast cancer cell viability, migration, and invasion in vitro and enhanced tumor growth and metastasis in vivo. It regulated EMT-related genes and bound to CXCR7 promoter to upregulate CXCR7 transcription. Both SOX4 and CXCR7 were highly expressed in human primary tumors and metastatic foci in lymph nodes. Treatment of breast cancer cells with the CXCR7 inhibitor CCX771 reversed the SOX4 effect on cell migration and invasion. Ectopic expression of SOX4 increased the susceptibility of cells to paclitaxel. Conclusions SOX4 plays an important role in the growth and metastasis of breast cancer. SOX4/CXCR7 may serve as potential therapeutic targets for the treatment. Paclitaxel may be a good therapeutic option if the expression level of SOX4 is high.

This study investigated the correlation between the Naples prognostic score (NPS), clinicopathological traits, and the postoperative prognoses of patients with triple-negative breast cancer (TNBC). Based on NPS, a predictive nomogram was developed to estimate the long-term survival probabilities of patients with TNBC post-surgery. We retrospectively examined the clinical records of 223 women with TNBC treated at Ningbo Medical Center, Lihuili Hospital between January 1, 2016 and December 31, 2020. Blood tests and biochemical analyses were conducted before surgery. The prognostic nutritional index (PNI), controlling nutritional status (CONUT), neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and NPS were determined based on blood-related markers. A Kaplan-Meier survival analysis assessed the association between NPS, PNI, CONUT score, overall survival (OS), and breast cancer-specific survival (BCSS). Predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) and C index. The patients were randomly divided into the training and the validation group (6:4 ratio). A nomogram prediction model was developed and evaluated using the R Software for Statistical Computing (RMS) package. NPS outperformed other scores in predicting inflammation outcomes. Patients with an elevated NPS had a poorer prognosis (P<0.001). Lymph node ratio (LNR), surgical method, postoperative chemotherapy, and NPS independently predicted OS, whereas M stage, LNR, and NPS independently predicted BCSS outcome. The OS and BCSS predicted by the nomogram model aligned well with the actual OS and BCSS. The decision curve analysis showed significant clinical utility for the nomogram model. In this study, NPS was an important prognostic indicator for patients with TNBC. The nomogram prognostic model based on NPS outperformed other prognostic scores for predicting patient prognosis. The model demonstrated a clear stratification ability for patient prognosis, which emphasized the potential benefits of early intervention for high-risk patients.

Approximately one-third of patients with HER2-positive breast cancer experienced recurrence within 10 years after receiving 1 year of adjuvant trastuzumab. The ExteNET study showed that 1 year of extended adjuvant neratinib after trastuzumab-based adjuvant therapy could reduce invasive disease-free survival (iDFS) events compared with placebo. This study investigated the efficacy and safety of pyrotinib, an irreversible pan-HER receptor tyrosine kinase inhibitor, after trastuzumab-based adjuvant therapy in patients with high-risk, HER2-positive early or locally advanced breast cancer. This multicenter phase II trial was conducted at 23 centers in China. After enrollment, patients received 1 year of extended adjuvant pyrotinib (400 mg/day), which should be initiated within 6 months after the completion of 1-year adjuvant therapy (trastuzumab alone or plus pertuzumab). The primary endpoint was 2-year iDFS rate. Between January 2019 and February 2022, 141 eligible women were enrolled and treated. As of October 10, 2022, the median follow-up was 24 (interquartile range, 18.0-34.0) months. The 2-year iDFS rate was 94.59% (95% confidence interval [CI]: 88.97-97.38) in all patients, 94.90% (95% CI: 86.97-98.06) in patients who completed 1-year treatment, 90.32% (95% CI: 72.93-96.77) in patients who completed only 6-month treatment, 96.74% (95% CI: 87.57-99.18) in the hormone receptor (HR)-positive subgroup, 92.77% (95% CI: 83.48-96.93) in the HR-negative subgroup, 96.88% (95% CI: 79.82-99.55) in the lymph node-negative subgroup, 93.85% (95% CI: 86.81-97.20) in the lymph node-positive subgroup, 97.30% (95% CI: 82.32-99.61) in patients with adjuvant trastuzumab plus pertuzumab, and 93.48% (95% CI: 86.06-97.02) in patients with adjuvant trastuzumab. The most common adverse events were diarrhea (79.4%), fatigue (36.9%), lymphocyte count decreased (36.9%), nausea (33.3%), and hand-foot syndrome (33.3%). Extended adjuvant pyrotinib administrated after trastuzumab-based adjuvant therapy showed promising efficacy in patients with high-risk HER2-positive breast cancer. The follow-up is ongoing to determine the long-term benefit. No external funding was received for this work. ClinicalTrials.gov: NCT05880927.

Background The association between subclinical hypothyroidism (SCH) and metabolic risk factors in the general health examination-based population has been widely explored. However, the results have been inconclusive. Additionally, the sex differences in the prevalence of SCH and the association of SCH with metabolic risk factors remain unknown. Methods We conducted this cross-sectional study using data from health examination-based participants between June 2016 and April 2018 in our health examination centre. Sex differences SCH and the association of SCH with metabolic risk factors were explored. Results The total prevalence of SCH was 3.40% among the 5319 included participants, and 4.90% among the 2306 female participants, which was much higher than the prevalence of 2.26% among the 3013 male participants ( p  < 0.05). In males, the difference between participants younger than 60 and aged 60 or older was not significant ( p  = 0.104); while in females, the difference between participants younger than 40 and participants aged 40 or older was statistically significant ( p  = 0.023). Multivariate logistic regression analysis demonstrated that age (OR = 0.568, p  = 0.004), body-mass index (BMI) (OR = 5.029, p  < 0.001) and systolic/diastolic blood pressure (SBP/DBP) (OR = 5.243, p  < 0.001) were independent predictors of SCH in females, but no metabolic risk factor was significantly associated with SCH in males. Further analysis revealed that the prevalence was much higher in participants with one or two metabolic risk factors than in those with no above metabolic risk factors regardless of age ( p  < 0.01). Conclusions Our study demonstrates that high BMI and/or high blood pressure are associated with SCH in female participants, and the prevalence of SCH among women with one or two metabolic risk factors ranges from 7.69–14.81%, which indicates that in such a population, serum concentrations of TSH and FT4 may be routinely screened in mainland China. Certainly, prospective, large-scale studies with long follow-up period are still necessary to further verify our results.

The interaction between SCAF4 and RNA polymerase II (POLR2A) is crucial for proper mRNA termination, with its dysregulation leading to truncated mRNAs and nonfunctional proteins, impairing cellular growth. Despite its potential relevance, the role of this interaction in triple‐negative breast cancer (TNBC) remains unexplored due to the lack of effective molecular tools. To address this, we employed SRiApt, an aptamer generated through the recently established Blocker‐SELEX pipeline. Its biological stability is improved by phosphorothioate modifications to form PTf‐SRiApt. Using this aptamer, the critical role of the SCAF4‐POLR2A interaction in driving TNBC tumor growth and immune regulation is uncovered. PTf‐SRiApt effectively inhibits tumor growth and induces cell cycle arrest in TNBC cells with elevated SCAF4 and POLR2A expression. Additionally, PTf‐SRiApt promotes premature mRNA termination, boosting antigen presentation and promoting T‐cell infiltration. Analysis of patient samples further confirmed the negative correlation between SCAF4‐POLR2A interaction and the effectiveness of immunotherapy, highlighting the potential of PTf‐SRiApt in improving immune efficacy. Together, the work provides a powerful tool not only for dissecting previously “undruggable” protein‐protein interactions but also for enhancing tumor immunogenicity and reshaping the tumor microenvironment. A phosphorothioate‐modified aptamer PTf‐SRiApt capable of disrupting “undruggable” transcription factor SCAF4‐POLR2A interaction with high inhibitory activity and biological stability is presented here. Through this inhibition, PTf‐SRiApt successfully arrested cell cycle progression, induced cell death, and elevated immune recruitment in SCAF4‐POLR2A‐high triple‐negative breast cancer. This novel inhibitor also demonstrated potential clinical efficacy in combination with immune checkpoint blockade in a wide range of cancers.