Human Epidermal Growth Factor Research Articles

Prognostic factors of patients with human epidermal growth factor receptor 2-positive breast cancer following neoadjuvant therapy: Development and validation of a predictive nomogram

ObjectiveHuman epidermal growth factor receptor 2 (HER2)–positive breast cancer exhibits an aggressive phenotype and poor prognosis. The application of neoadjuvant therapy (NAT) in patients with breast cancer can significantly reduce the risks of disease recurrence and improve survival. By integrating different clinicopathological factors, nomograms are valuable tools for prognosis prediction. This study aimed to assess the prognostic value of clinicopathological factors in patients with HER2-positive breast cancer and construct a nomogram for outcome prediction. MethodsWe retrospectively analyzed the clinicopathological data from 374 patients with breast cancer admitted to the Fourth Hospital of Hebei Medical University between January 2009 and December 2017, who were diagnosed with invasive breast cancer through preoperative core needle biopsy pathology, underwent surgical resection after NAT, and were HER2-positive. Patients were randomly divided into a training and validation set at a ratio of 7:3. Univariate and multivariate survival analyses were performed using Kaplan-Meier and Cox proportional hazards regression models. Results of the multivariate analysis were used to create nomograms predicting 3-, 5-, and 8-year overall survival (OS) rates. Calibration curves were plotted to test concordance between the predicted and actual risks. Harrell C-index and time-dependent receiver operating characteristic (ROC) curves were used to evaluate the discriminability of the nomogram prediction model. ResultsAll included patients were women, with a mean age of 50 ± 10.4 years (range: 26–72 years). In the training set, both univariate and multivariate analyses identified residual cancer burden (RCB) class, tumor-infiltrating lymphocytes(TILs), and clinical stage as independent prognostic factors for OS, and these factors were combined to construct a nomogram. The calibration curves demonstrated good concordance between the predicted and actual risks, and the C-index of the nomogram was 0.882 (95 % CI 0.863–0.901). The 3-, 5-, and 8-year areas under the ROC curve (AUCs) were 0.909, 0.893, and 0.918, respectively, indicating good accuracy of the nomogram. The calibration curves also demonstrated good concordance in the validation set, with a C-index of 0.850 (95 % CI 0.804–0.896) and 3-, 5-, and 8-year AUCs of 0.909, 0.815, and 0.834, respectively, which also indicated good accuracy. ConclusionThe nomogram prediction model accurately predicted the prognostic status of post-NAT patients with breast cancer and was more accurate than clinical stage and RCB class. Therefore, it can serve as a reliable guide for selecting clinical treatment measures for breast cancer.

Targeting Hypoxia and HIF1α in Triple-Negative Breast Cancer: New Insights from Gene Expression Profiling and Implications for Therapy.

Breast cancer is a complex and multifaceted disease with diverse risk factors, types, and treatment options. Triple-negative breast cancer (TNBC), which lacks the expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2), is the most aggressive subtype. Hypoxia is a common feature of tumors and is associated with poor prognosis. Hypoxia can promote tumor growth, invasion, and metastasis by stimulating the production of growth factors, inducing angiogenesis, and suppressing antitumor immune responses. In this study, we used mRNA-seq technology to systematically investigate the gene expression profile of MDA-MB-231 cells under hypoxia. We found that the hypoxia-inducible factor (HIF) signaling pathway is the primary pathway involved in the cellular response to hypoxia. The genes in which expression levels were upregulated in response to hypoxia were regulated mainly by HIF1α. In addition, hypoxia upregulated various genes, including Nim1k, Rimkla, Cpne6, Tpbgl, Kiaa11755, Pla2g4d, and Ism2, suggesting that it regulates cellular processes beyond angiogenesis, metabolism, and known processes. We also found that HIF1α was hyperactivated in MDA-MB-231 cells under normoxia. A HIF1α inhibitor effectively inhibited the invasion, migration, proliferation, and metabolism of MDA-MB-231 cells. Our findings suggest that hypoxia and the HIF signaling pathway play more complex and multifaceted roles in TNBC than previously thought. These findings have important implications for the development of new therapeutic strategies for TNBC.

Advances in the treatment of human epidermal growth factor receptor 2-positive gastric cancer.

Human epidermal growth factor receptor 2 has been a pivotal biomarker for gastric cancer treatment strategies for many years. However, more than a decade after the ToGA trial demonstrated the efficacy of trastuzumab in improving survival, the development of treatments targeting human epidermal growth factor receptor 2 remains challenging. Several large-scale clinical trials of tyrosine kinase inhibitors, non-trastuzumab anti-human epidermal growth factor receptor 2 antibodies, and antibody-drug conjugates have failed to meet the primary endpoints. The concept of trastuzumab beyond progression and the complexity of resistance mechanisms to anti-human epidermal growth factor receptor 2 therapy after trastuzumab treatment presented significant obstacles, leading to trastuzumab being the sole therapy for human epidermal growth factor receptor 2-positive gastric cancer for some time. Nevertheless, the landscape has shifted in recent years, especially since the introduction of the antibody-drug conjugate trastuzumab deruxtecan in 2020. This has rekindled the interest in developing treatments targeting human epidermal growth factor receptor 2 in gastric cancer.

Targeted Nanocarrier-Based Drug Delivery Strategies for Improving the Therapeutic Efficacy of PARP Inhibitors against Ovarian Cancer.

The current focus of ovarian cancer (OC) research is the improvement of treatment options through maximising drug effectiveness. OC remains the fifth leading cause of cancer-induced mortality in women worldwide. In recent years, nanotechnology has revolutionised drug delivery systems. Nanoparticles may be utilised as carriers in gene therapy or to overcome the problem of drug resistance in tumours by limiting the number of free drugs in circulation and thereby minimising undesired adverse effects. Cell surface receptors, such as human epidermal growth factor 2 (HER2), folic acid (FA) receptors, CD44 (also referred to as homing cell adhesion molecule, HCAM), and vascular endothelial growth factor (VEGF) are highly expressed in ovarian cancer cells. Generation of active targeting nanoparticles involves modification with ligands that recognise cell surface receptors and thereby promote internalisation by cancer cells. Several poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently used for the treatment of high-grade serous ovarian carcinomas (HGSOC) or platinum-sensitive relapsed OC. However, PARP resistance and poor drug bioavailability are common challenges, highlighting the urgent need to develop novel, effective strategies for ovarian cancer treatment. This review evaluates the utility of nanoparticles in ovarian cancer therapy, with a specific focus on targeted approaches and the use of PARPi nanocarriers to optimise treatment outcomes.

Human epidermal growth factor 2 (HER2) amplification in uterine serous carcinoma: an analysis of prognosis and immune microenvironment.

Uterine serous carcinoma (USC) is a biologically aggressive subtype of endometrial cancer. Anti-human epidermal growth factor receptor 2 (HER2) therapy has demonstrated its promising effects on HER2-positive USC. However, data on prognostic relevance and immune microenvironment are limited in HER2-positive USC. This study aimed to determine the clinicopathologic features, prognosis, and the immune microenvironment trait in HER2 status in USC. We applied immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and multi-color immunofluorescence to investigate HER2 expression and amplification, PD-L1 expression, and tumor infiltration lymphocytes (TIL) in 77 USC (61 pure and 16 mixed-type USC). HER2 IHC 1 + , 2 + , and 3 + were found in 26, 18, and 10 USC, respectively. HER2 staining frequently had an incomplete membrane (basolateral or "U"-shaped) pattern. Twenty-three cases (23/54, 42.6%) showed an intra-tumor heterogeneous staining. HER2 amplification was present in 16/77 (20.8%) USC. HER2 amplification was significantly associated with deep myometrial invasion (> 1/2), and increased intra-epithelial and stromal density of CD20 + or CD8 + TIL (all P < 0.05), but not with USC subtypes (pure versus mixed-type), PD-L1 expression, CD4 + TIL, CD68 + histiocytes, or the CD4 + /CD8 + ratio (p > 0.05). HER2 amplification was associated with poor overall and progression-free survival in USC, but lost the prognostic significance on multivariate analysis. We concluded that HER2 amplified USC had adverse clinical outcomes, but showed the potential active immune microenvironment. Our findings raised the possibility of the combined anti-HER2 and immunotherapy for HER2-positive USC in the future.

Quantitative comparison of immunohistochemical HER2-low detection in an interlaboratory study.

Recently, human epidermal growth factor 2 (HER2)-low (i.e. HER2 score 1+ or 2+ without amplification) breast cancer patients became eligible for trastuzumab-deruxtecan treatment. To improve assay standardisation and detection of HER2-low in a quantitative manner, we conducted an external quality assessment-like study in the Netherlands. Dynamic range cell lines and immunohistochemistry (IHC) calibrators were used to quantify HER2 expression and to assess interlaboratory variability. Three blank slides with a dynamic range cell line and an IHC calibrator were stained with routine HER2 assays by 35 laboratories. Four different antibody clones were used: 19 (54.3%) 4B5, six (17.1%) A0485, five (14.3%) DG44 (HercepTest) and five (14.3%) SP3. Laboratories used two different detection kits for 4B5 assays: 14 (73.7%) ultraView and five (26.3%) OptiView. Variability of HER2 expression in cell lines, measured with artificial intelligence software, was median (min-max) = negative core 0.5% (0.0-57.0), 1+ core 4.3% (1.6-71.3), 2+ core 42.8% (30.4-92.6) and 3+ core 96.2% (91.8-98.8). The calibrators DG44 and 4B5 OptiView had the highest analytical sensitivity, closely followed by 4B5 ultraView. SP3 was the least sensitive. Calibrators of A0485 assays were not analysable due to background staining. As assays were validated for detecting HER2-amplified tumours, not all assays and antibodies proved suitable for HER2-low detection. Some tests showed distinct expression in the negative cell line. Dynamic range cell line controls and quantitative analysis using calibrators demonstrated more interlaboratory variability than commonly appreciated. Revalidation of HER2 tests by laboratories is needed to ensure clinical applicable HER2-low assays.

Emerging Therapeutic Targets and Future Directions in Advanced Gastric Cancer: A Comprehensive Review.

Metastatic gastric cancer (GC) still represents a critical clinical challenge, with limited treatment options and a poor prognosis. Most patients are diagnosed at advanced stages, limiting the chances of surgery and cure. The identification of molecular targets and the possibility of combining immune checkpoint inhibitors with chemotherapy have recently reshaped the therapeutic landscape of metastatic gastric cancer. The new classification of gastric cancer, mainly based on immunologic and molecular criteria such as programmed cell death 1 (PD-1), microsatellite instability (MSI), and human epidermal growth factor receptor 2 (HER2), has made it possible to identify and differentiate patients who may benefit from immunotherapy, targeted therapy, or chemotherapy alone. All relevant and available molecular and immunological targets in clinical practice for the systemic treatment of this disease are presented. Particular attention is given to possible future approaches, including circulating tumor DNA (ctDNA) for therapeutic monitoring, new targeting agents against molecular pathways such as fibroblast growth factor receptor (FGFR) and MET, chimeric antigen receptor (CAR)-T cells, and cancer vaccines. This review aims to provide a comprehensive understanding of current targets in advanced gastric cancer and to offer valuable insights into future directions of research and clinical practice in this challenging disease.

Nerve growth factor inducible (VGF) is a secreted mediator for metastatic breast cancer tropism to the brain.

Brain metastases are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we studied the impact of brain organotropic BC cells' secretomes on the establishment of the brain pre-metastatic niche (PMN). We found that BC cells with specific tropism to the brain caused significant blood-brain barrier (BBB) disruption, as well as microglial activation, in both in vitro and in vivo models. Further, we searched for a brain-organotropic metastatic signature, as a promising source for the discovery of new biomarkers involved in brain metastatic progression. Of relevance, we identified VGF (nerve growth factor inducible) as a key mediator in this process, also impacting the BBB and microglial functions both in vitro and in vivo. In a series of human breast tumors, VGF was found to be expressed in both cancer cells and the adjacent stroma. Importantly, VGF-positive tumors showed a significantly worse prognosis and were associated with HER2 (human epidermal growth factor receptor 2) overexpression and triple-negative molecular signatures. Further clinical validation in primary tumors from metastatic BC cases showed a significant association between VGF and the brain metastatic location, clearly and significantly impacting on the prognosis of BC patients with brain metastasis. In conclusion, our study reveals a unique secretome signature for BC with a tropism for the brain, highlighting VGF as a crucial mediator in this process. Furthermore, its specific impact as a poor prognostic predictor for BC patients with brain metastasis opens new avenues to target VGF to control the progression of brain metastatic disease. © 2024 The Pathological Society of Great Britain and Ireland.

An Investigation on Breast Cancer Knowledge in Developing Nations

Breast cancer is the most common malignant tumor in women diagnosed globally and the leading cause of cancer-related death. Globally, the prevalence of breast cancer is increasing with time. Globally, breast cancer is the most prevalent type of cancer. The incidence of breast cancer is linked to several risk factors, such as genetic and inherited predispositions. Breast cancers can be of many different forms. The molecular features of breast cancer, such as the activation of hormone receptors (PR, ER, and HER2) and human epidermal growth factor receptor 2, genetic alterations (BRCA1/2 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA] mutations), and immune system markers (PD L1, tumour-infiltrating lymphocytes [TIL], and programmed death-ligand 1 [PD L1]) may impact treatment strategies. sufferers.

Immunohistochemical Expression of Cyclooxygenase 2 (COX-2) as a Prognostic Marker and Its Correlation With Clinicopathological Parameters in Breast Cancer.

Introduction Breast cancer is considered the most common cancer among women. According to the literature, cyclooxygenase-2 (COX-2) expression in breast carcinoma is associated with aggressive tumor biology and acts as an independent prognostic marker. As COX-2 is a newly identified marker, studies are required to understand its immunoexpression and correlation with hormone receptor status and other prognostic factors, which helps in the therapeutic management of patients. Hence, this study evaluates the expression of COX-2 in breast carcinoma. Methods A hospital-based cross-sectional study was done on 55 mastectomy specimens collected at the Histopathology and Surgical Pathology Section of the Department of Pathology. The patient's age, histological type, tumor size, lymph node status, histological grade, and vascular invasion were noted. Immunohistochemical staining for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2/neu protooncogene (HER2/neu), and COX-2 markers was performed, and its results were compared with these clinicopathological and prognostic parameters. Results were subjected to statistical analysis. Results COX-2 expression was seen in 37 out of 55 cases (67.2%). Expression of COX-2 showed a statistically significant correlation with vascular invasion, ER-negative status, and PR-negative status. No statistical association was found between other parameters like age, tumor size, histological type, histological grade, lymph node status, and HER2/neu status. Conclusion The expression of COX-2 correlated strongly with well-established poor prognostic markers, such as vascular invasion, ER-negative status, and PR-negative status. Thus, expression of COX-2 suggests aggressive tumor biology, and it can be used as an independent prognostic marker.

Density of tertiary lymphoid structures predicts clinical outcome in breast cancer brain metastasis

BackgroundPatients with breast cancer brain metastases (BCBM) experience a rapid decline in their quality of life. Recently, tertiary lymphoid structures (TLSs), analogs of secondary lymphoid organs, have attracted extensive attention....

The impact of human epidermal growth factor receptor-2 (low) status on the efficacy of first line cyclin-dependent kinase 4/6 inhibitors in advanced breast cancer.

The fact that the human epidermal growth factor receptor 2 (HER2)-low group, historically classified as HER2 negative in breast cancer histology, benefited from HER2-targeted treatments similarly to the HER2-positive group indicates that this group has a distinct histology from the HER2-0 group. The effectiveness of cyclin-dependent kinase 4/6 inhibitors, which are the standard first-line treatment for hormone receptor-positive, HER2-negative advanced breast cancer, in this newly defined histological subgroup remains a topic of debate. In our study, we examined the impact of HER2 status on the efficacy of CDK4/6 inhibitors. Our study is a retrospective, multicenter, real-world data analysis. One hundred sixty patients were included in the study. The relationship between HER2 status and other clinical-pathological features, as well as progression-free survival, was examined. Median follow-up was 20.33 ± 0.98 months. The mPFS could not be reached. All patients exhibited positive estrogen receptor expression. Among the patients, 111 (69.4%) were categorized as HER2-0, and 49 (30.6%) as HER2-low. The 24-month progression-free survival rates were similar between HER2-0 and HER2-low patients (60.6% vs 65.3%, hormone receptor: 1.18, CI: 0.67-2.20, P = .554). We established that the mPFS achieved with cyclin-dependent kinase 4/6 inhibitors as a first-line therapy for patients with advanced breast cancer is unaffected by HER2 status.

Exploring SALL4 as a significant prognostic marker in breast cancer and its association with progression pathways involved in cancer genesis

Breast carcinoma is the leading factor in women's cancer-related fatalities. Due to its numerous inherent molecular subtypes, breast cancer is an extremely diverse illness. The human epidermal growth factor receptor 2 (HER2) positive subtypes stands out among these subtypes as being especially prone to cancer development and illness recurrence. The regulation of embryonic stem cells' pluripotency and self-renewal is carried out by the SALL4 (Spalt-like transcription factor 4) family member. Numerous molecular pathways operating at the transcriptional, post-transcriptional, and epigenomic levels regulate the expression of SALL4. Many transcription factors control the expression of SALL4, with STAT3 being the primary regulator in hepatocellular carcinoma (HCC) and breast carcinoma. Moreover, this oncogene has been connected to a number of cellular functions, including invasion, apoptosis, proliferation, and resistance to therapy. Reduced patient survival rates and a worse prognosis have been linked to higher levels of SALL4. In order to target the undruggable SALL4 that is overexpressed in breast carcinoma, we investigated the prognostic levels of SALL4 in breast carcinoma and its interaction with various related proteins. Using TIMER 2.0 analysis, the expression pattern of SALL4 was investigated across all TCGA datasets. The research revealed that SALL4 expression was elevated in various cancers. The UALCAN findings demonstrated that SALL4 was overexpressed in all tumor samples including breast cancer especially TNBC (Triple negative breast cancer). The web-based ENRICHR program was used for gene ontology analysis that revealed SALL4 was actively involved in the development of the nervous system, positive regulation of stem cell proliferation, regulation of stem cell proliferation, regulation of the activin receptor signaling pathway, regulation of transcription using DNA templates, miRNA metabolic processes, and regulation of transcription by RNA Polymerase I. Using the STRING database, we analyzed the interaction and involvement of SALL4 with other abruptly activated proteins and used Cytoscape 3.8.0 for visualization. Additionally, using bc-GenExMiner, we studied the impact of SALL4 on pathways abruptly activated in different breast cancer subtypes that revealed SALL4 was highly correlated with WNT2B, NOTCH4, AKT3, and PIK3CA. Furthermore, to target SALL4, we evaluated and analyzed the impact of CLP and its analogues, revealing promising outcomes.

In silico evaluation of potential breast cancer receptor antagonists from GC-MS and HPLC identified compounds in Pleurotus ostreatus extracts.

Introduction: Pharmacotherapeutic targets for breast cancer include the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (EGFR). Inhibitors of these receptors could be interesting therapeutic candidates for the treatment and management of breast cancer (BC). Aim: This study used GC-MS and HPLC to identify bioactive compounds in Pleurotus ostreatus (P. ostreatus) extracts and applied in silico methods to identify potent EGFR, ER, and PR inhibitors from the compounds as potential drug candidates. Method: GC-MS and HPLC were used to identify bioactive chemicals in P. ostreatus extracts of aqueous (PO-A), methanol (PO-M), ethanol (PO-E), chloroform (PO-C), and n-hexane (PO-H). The ER, PR, and EGFR model optimization and molecular docking of compounds/control inhibitors in the binding pocket were simulated using AutoDock Vina in PyRx. The drug-likeness, pharmacokinetic, and pharmacodynamic features of prospective docking leads were all anticipated. Result: The results indicated the existence of 29 compounds in PO-A, 36 compounds in PO-M and PO-E, 42 compounds in PO-C, and 22 compounds in PO-H extracts. With ER, only o-tolylamino-acetic acid (4-nitro-benzylidene)-hydrazide (-7.5 kcal mol-1) from the ethanolic extract could bind to the receptor. PR and EGFR, on the other hand, identified several compounds with higher binding affinities than the control. Ergotaman-3',6',18-trione (-8.1 kcal mol-1), 5,10-diethoxy-2,3,7,8-tetrahydro-1H,6H-dipyrrolo[1,2-a:1',2'-d]pyrazine (-7.8 kcal mol-1) from the aqueous extract; o-tolylamino-acetic acid (4-nitro-benzylidene)-hydrazide (-8.4 kcal mol-1) from the ethanolic extract had better binding affinity compared to progesterone (-7.7 kcal mol-1). Likewise, ergotaman-3',6',18-trione (-9.7 kcal mol-1) from the aqueous extract and phenol, 2,4-bis(1,1-dimethyl ethyl) (-8.2 kcal mol-1) from the chloroform extract had better binding affinities compared to the control, gefitinib (-7.9 kcal mol-1) with regards to EGFR. None of the PO-H or PO-M extracts outperformed the control for any of the proteins. Phenols and flavonoids such as quercetin, luteolin, rutin, chrysin, apigenin, ellagic acid, and naringenin had better binding affinity to PR and EGFR compared to their control. Conclusion: The identified compounds in the class of phenols and flavonoids were better lead molecules due to their ability to strongly bind to the proteins' receptors. These compounds showed promising drug-like properties; they could be safe and new leads for creating anticancer medicines.

Characteristics of Invasive Cribriform Carcinoma

Invasive cribriform carcinoma (ICC) is a type of malignant tumor with slow growth and good prognosis. The study was a single center retrospective study. The percentage of ICC among patients diagnosed with breast cancer was 0.3% (8/2454 patients). All patients tested positive for estrogen or progesterone receptors and 12.5% (1/8) patients tested positive for human epidermal growth factor receptor type2 (HER2). The present study suggests that the clinicopathological features of ICC are low-grade hormone receptor-positive luminal type with a good prognosis. However, some patients were HER2-positive and require careful follow-up.

Risk of radionecrosis in HER2-positive breast cancer with brain metastasis receiving trastuzumab emtansine (T-DM1) and brain stereotactic radiosurgery

ObjectivesTo investigate the potential relationship between trastuzumab emtansine (T-DM1) treatment and radionecrosis induced by brain stereotactic radiosurgery (SRS) in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Materials and MethodsPatients with HER2-positive breast cancer who were diagnosed with brain metastasis and received both SRS and HER2-targeted agents between 2012 and 2022 were retrospectively analyzed. Patients who received T-DM1 within 1 year (either before or after) of SRS were considered as ‘T-DM1 exposure (+)’. T-DM1 exposure (−) group had other HER2-targeted agents or received T-DM1 more than 1 year before or after SRS. Symptomatic radionecrosis was defined as Common Terminology Criteria for Adverse Events grade 2 or greater. ResultsA total of 103 patients with 535 treatment sessions were included from seven tertiary medical centers in Korea and Italy. The median follow-up duration was 15.5 months (range 1.1–101.9). By per-patient analysis, T-DM1 exposure (+) group had an increased risk of overall radionecrosis after multivariate analysis (HR 2.71, p = 0.020). Additionally, T-DM1 exposure (+) group was associated with a higher risk of symptomatic radionecrosis compared to T-DM1 exposure (−) patients (HR 4.34, p = 0.030). In per-treatment analysis, T-DM1 exposure (+) was linked to higher incidences of overall (HR 3.13, p = 0.036) and symptomatic radionecrosis (HR 10.4, p = 0.013) after multivariate analysis. A higher prevalence of radionecrosis was observed with T-DM1 exposure (+) and a previous history of whole brain radiotherapy. ConclusionAn increased risk of radionecrosis was observed in patients receiving T-DM1 with brain SRS. Further research is needed to better understand the optimal sequence and interval for administering T-DM1 and SRS.

GluOC promotes proliferation and metastasis of TNBC through the ROCK1 signaling pathway

BackgroundTriple negative breast cancer (TNBC) is a type of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, is highly malignant and aggressive, lacks of corresponding targeted therapy, and has a relatively poor prognosis. Therefore, understanding the mechanism of TNBC development and formulating effective treatment strategies for inducing cell death are still urgent tasks in the treatment of TNBC. Research has shown that uncarboxylated osteocalcin can promote the proliferation of prostate cancer, lung adenocarcinoma and TNBC cells, but the mechanism by which GluOC affects TNBC growth and metastasis needs further study.MethodsMDA-MB-231 breast cancer cells were used for in vitro cell analysis. Key target molecules or pathways were identified by RNA sequencing, and migration ability was detected by scratch assays, Transwell assays, cell adhesion assays and western blot analysis. Fluorescence staining, colony detection, qRT‒PCR and flow cytometry were used to detect apoptosis, oxidative stress, the cell cycle and the stemness of cancer cells, and a xenotransplantation model in BALB/C nude mice was used for in vivo analysis.ResultsThis study demonstrated that GluOC facilitates the migration of MDA-MB-231 breast cancer cells through the ROCK1/MYPT1/MLC2 signalling pathway and promotes the proliferation of TNBC cells via the ROCK1/JAK2/PIK3CA/AKT signalling pathway. Experiments in nude mice demonstrated that GluOC promoted tumour cell proliferation and metastasis in tumour-bearing mice, which further clarified the molecular mechanism of TNBC growth and invasion.ConclusionOur findings highlight the importance of GluOC in driving TNBC progression and its association with poor patient outcomes. This study clarifies the functional effects of GluOC on TNBC growth, providing insight into the molecular basis of TNBC and potentially providing new ideas for developing targeted therapies to improve patient outcomes.

Histogenetic insights and genetic landscape of fibromatosis-like undifferentiated gastric carcinoma: a focused study

BackgroundThe aim of this study was to elucidate the histogenesis and genetic underpinnings of fibromatosis-like undifferentiated gastric carcinoma (FLUGC), a rare pathological entity.MethodThrough a detailed analysis of seven cases, including histopathological evaluation, CTNNB1 gene mutation screening, human epidermal growth factor receptor 2 (HER2) protein level quantification, and HER2 gene amplification assessment to identify the pathological and molecular characteristics of FLUGC.ResultsOf the seven patients in this study, five were male and two were female (age: 39–73 years). Four patients presented with lesions in the gastric antrum and three had lesions in the lateral curvature of the stomach. Histopathologically, over 90% of the tumor consisted of aggressive fibromatosis-like tissue, including proliferating spindle fibroblasts and myofibroblasts and varying amounts of collagenous fibrous tissues. Undifferentiated cancer cells, accounting for less than 10%, were dispersed among the aggressive fibromatosis-like tissues. These cells were characterized by their small size and were relatively sparse without glandular ducts or nested mass-like structures. Immunophenotyping results showed positive expression of CKpan, CDX2, villin, and p53 in undifferentiated cancer cells; positive expression of vimentin in aggressive fibromatosis-like tissue; positive cytoplasmic expression of β-catenin; and focal cytoplasmic positive expression of smooth muscle actin (SMA). Genetic analysis did not reveal any mutations in the CTNNB1 gene test, nor was there amplification in the HER2 gene fluorescence in situ hybridization (FISH) test. Additionally, the Epstein-Barr encoding region (EBER) of in situ hybridization was negative; and the mismatch repair (MMR) protein was positive. Programmed cell death-1 (PD-1) was < 1–5%; programmed cell death ligand 1 (PD-L1): TPS = 1–4%, CPS = 3–8.ConclusionThe study highlights the significance of CTNNB1, HER2, EBER, and MMR as pivotal genetic markers in FLUGC, underscoring their relevance for diagnosis and clinical management. The rarity and distinct pathological features of FLUGC emphasize the importance of accurate diagnosis to prevent underdiagnosis or misdiagnosis and to raise awareness within the medical community.

Prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer.

This study aimed to determine the prognostic value and microenvironmental crosstalk of exosome-related signatures in human epidermal growth factor receptor 2 positive breast cancer (HER2+ BC). Transcriptome sequencing and clinicopathological data were downloaded from the Cancer Genome Atlas. The 10X single cell sequencing dataset was downloaded from the National Center for Biotechnology Information Gene Expression Omnibus. Exosomes-Related Genes were extracted from the ExoCarta and Gene Set Enrichment Analysis databases. FGF9, SF3B4, and EPCAM were found and deemed the most accurate predictive signatures. Patients with HER2+ BC were subtyped into three groupings by exosome prognostic gene (EPGs). The expression of SF3B4 was positively linked with the infiltration of macrophages, neutrophils, and CD4+ T cells. The expression characteristics of EPGs were associated with the biological process of "response to xenobiotic stimuli." Interactions were relatively high between malignant epithelial cells and fibroblasts, endothelial cells, monocytes, and macrophages. Malignant epithelial cells interact more with fibroblasts and endothelial cells. The migration inhibitory factor pathway was the primary outgoing signaling pattern, while the C-C motif chemokine ligand pathway was the primary incoming signaling pattern for communication between malignant epithelial cells and macrophages. This study described the role of exosome signatures in the prognosis and microenvironment of HER2+ BC and provided a basis for future research.

Low testing rates and high BRCA prevalence: Poly (ADP-ribose) polymerase inhibitor use in Middle East BRCA/homologous recombination deficiency-positive cancer patients.

Poly (ADP-ribose) polymerase inhibitors (PARPis) are approved as first-line therapies for breast cancer gene (BRCA)-positive, human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer. They are also effective for new and recurrent ovarian cancers that are BRCA- or homologous recombination deficiency (HRD)-positive. However, data on these mutations and PARPi use in the Middle East are limited. To assess BRCA/HRD prevalence and PARPi use in patients in the Middle East with breast/ovarian cancer. This was a single-center retrospective study of 57 of 472 breast cancer patients tested for BRCA mutations, and 25 of 65 ovarian cancer patients tested for HRD. These adult patients participated in at least four visits to the oncology service at our center between August 2021 and May 2023. Data were summarized using descriptive statistics and compared using counts and percentages. Response to treatment was assessed using Response Evaluation Criteria in Solid Tumors criteria. Among the 472 breast cancer patients, 12.1% underwent BRCA testing, and 38.5% of 65 ovarian cancer patients received HRD testing. Pathogenic mutations were found in 25.6% of the tested patients: 26.3% breast cancers had germline BRCA (gBRCA) mutations and 24.0% ovarian cancers showed HRD. Notably, 40.0% of gBRCA-positive breast cancers and 66.0% of HRD-positive ovarian cancers were Middle Eastern and Asian patients, respectively. PARPi treatment was used in 5 (33.3%) gBRCA-positive breast cancer patients as first-line therapy (n = 1; 7-months progression-free), for maintenance (n = 2; > 15-months progression-free), or at later stages due to compliance issues (n = 2). Four patients (66.6%) with HRD-positive ovarian cancer received PARPi and all remained progression-free. Lower testing rates but higher BRCA mutations in breast cancer were found. Ethnicity reflected United Arab Emirates demographics, with breast cancer in Middle Eastern and ovarian cancer in Asian patients.