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Background Breast cancer has recently increased in post-menopausal Iraqi women. In Western countries at high-risk for breast cancer, there is a bimodal increase in estrogen receptor (ER) positive tumors with a peak of low proliferation rate luminal A over higher proliferation rate luminal B tumors after 60 years of age. The aim of this study was to analyze in Iraqi women whether shifts are occurring in immunohistochemical (IHC) surrogates of molecular breast cancer subtypes toward a high-risk profile. Methods Age specific and age standardized womens breast cancer incidence was estimated for the years 2006 through 2012. IHC results of ER, PR, HER2, and Ki67 testing were analyzed on the breast cancers of 125 Arabic and 725 Kurdish women by frequency of distribution and by age. Results Between 2006 and 2012, age standardized incidence of breast cancer in Iraq increased from 30 to 40/100,000 women with the increase specifically occurring in women ≥ 60 years old ( P  < 0.001). Breast cancers in Kurdish women ≥ 60 years old may also have increased ( P  = 0.047) with urban exceeding rural rates by 2:1. For both Kurdish and Arabic women, there was a marked predominance of luminal B tumors at all ages in which luminal B and luminal A tumors were asymmetric skewed toward older age but with no late luminal A age peak. Conclusions Older Iraqi women do not show the bimodal shift toward higher rates of luminal A breast cancers seen in the West. The modest increase in age standardized incidence of breast cancer in Iraqi is being seen specifically in older women and may be better attributed to a trend for care in urban cancer centers rather than changing tumor characteristics.

Background Residual breast cancer after neo-adjuvant chemotherapy (NACT) predicts disease outcome and is a surrogate for survival in aggressive breast cancer (BC) subtypes. Pathological complete response (pCR) rate, however, is lower for luminal B BC in comparison to the triple negative (TNBC) and HER2+ subtypes. The addition of immune checkpoint blockade (ICB) to NACT has the potential to increase pCR rate but is hampered by the lower immunogenicity of luminal B BC. Novel strategies are needed to stimulate the immune response and increase the response rate to ICB in luminal B BC. Methods The Neo-CheckRay trial is a randomized phase II trial investigating the impact of stereotactic body radiation therapy (SBRT) to the primary breast tumor in combination with an anti-CD73 (oleclumab) to increase response to anti PD-L1 (durvalumab) and NACT. The trial is designed as a three-arm study: NACT + SBRT +/− durvalumab +/− oleclumab. The result at surgery will be evaluated using the residual cancer burden (RCB) index as the primary endpoint. Six patients will be included in a safety run-in, followed by a randomized phase II trial that will include 136 evaluable patients in 3 arms. Inclusion is limited to luminal B breast cancers that are MammaPrint genomic high risk. Discussion combination of ICB with chemotherapy in luminal B BC might benefit from immune priming agents to increase the response rate. As none have been identified so far, this phase II trial will evaluate SBRT and oleclumab as potential immune priming candidates. Trial registration trial registered on ClinicalTrials.gov ( NCT03875573 ) on March 14th, 2019.

Background After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR, and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue. Methods In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR. Results Strikingly, we found that aberrantly decreasing IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA-binding protein expression and changes in tissue composition are among the causes of aberrantly decreasing IR in BrCa. Conclusions Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.

Chromosomal instability (CIN), defined by variations in the number or structure of chromosomes from cell to cell, is recognized as a distinctive characteristic of cancer associated with the ability of tumors to adapt to challenging environments. CIN has been recognized as a source of genetic variation that leads to clonal heterogeneity (CH). Recent findings suggest a potential association between CIN and CH with the prognosis of BC patients, particularly in tumors expressing the epidermal growth factor receptor 2 (HER2+). In fact, information on the role of CIN in other BC subtypes, including luminal B BC, is limited. Additionally, it remains unknown whether CIN in luminal B BC tumors, above a specific threshold, could have a detrimental effect on the growth of human tumors or whether low or intermediate CIN levels could be linked to a more favorable BC patient prognosis when contrasted with elevated levels. Clarifying these relationships could have a substantial impact on risk stratification and the development of future therapeutic strategies aimed at targeting CIN in BC. This study aimed to assess CIN and CH in tumor tissue samples from ten patients with luminal B BC and compare them with established clinicopathological parameters. The results of this study reveal that luminal B BC patients exhibit intermediate CIN and stable aneuploidy, both of which correlate with lymphovascular invasion. Our results also provide valuable preliminary data that could contribute to the understanding of the implications of CIN and CH in risk stratification and the development of future therapeutic strategies in BC.

Luminal subtype B breast cancer represents a clinically challenging subtype, accounting for nearly 40% of all breast cancers. However, clinical outcomes remain suboptimal due to challenges such as poor solubility, resistance, and drug-induced toxicity. In our previous work, a synthesized compound pyrazoline B demonstrated potent toxicity effects towards T47D, 4T1, and Hs578T breast cancer cells, WiDr colorectal cancer cells, and HeLa cervical cancer cells. Building on these findings, we now investigate-for the first time-the therapeutic potential of a lead compound, pyrazoline B, against luminal B breast cancer using the clinically relevant BT-474 model (HER2+/ER+). This study systematically evaluates pyrazoline B's standalone efficacy and preliminary synergistic interactions with paclitaxel, aiming to address current therapeutic gaps in this high-risk subtype. Comprehensive in vitro analysis included proliferation and cell migration (scratch) assays, flow cytometry (apoptosis and cell cycle), ELISA (EGFR/VEGFR-2), and RT-qPCR, complemented by in silico ADME and molecular docking analyses. Pyrazoline B demonstrated multimodal activity, inducing G0/G1 arrest through Cyclin D1 suppression while reduced EGFR and VEGFR-2 proteins level. The compound triggered caspase-independent cell death via oxidative stress. Additionally, pyrazoline B enhances the inhibitory effect of paclitaxel on the proliferation and migration of cancer cells. ADME predictions revealed that pyrazoline B exhibits more favorable pharmacokinetic properties of than paclitaxel. Our findings established pyrazoline B as a first-in-class multi-target agent against BT-474 luminal B breast cancer, uniquely capable of simultaneously disrupting cell cycle progression, growth factor signaling, and redox homeostasis. Pyrazoline B demonstrates strong potential as a monotherapy, and our initial combination screening showed promising boosting effects when used with existing therapies. Future studies should prioritize: mechanistic synergy studies and in vivo validation to assess translational potential.

Background Breast cancer (BC) is the most common malignancy in women and the second leading cause of cancer-related death; chemoresistance is still a clinical challenge mainly because of the different molecular features of this kind of tumour. Doxorubicin (Doxo) is widely used despite its adverse effects and the common onset of resistance. Chaperone-Mediated Autophagy (CMA) has been identified as an important mechanism through which chemotherapeutics can exert their cytotoxic effects and, in this context, LAMP-2A, the key player of CMA, can be a useful biomarker. Methods A cohort of patients and breast cancer cells have been screened for Doxo effect and CMA activation by analysing the LAMP-2A level. Molecular silencing has been used to clarify CMA role in BC responsiveness to treatments. Low Doxo doses were combined with other drugs (TMZ or PX-478, a HIF-1α inhibitor) to evaluate their cytotoxic ability and their role in modulating CMA. Results In this paper, we showed that CMA is an important mechanism mediating the responsiveness of breast cancer cell to different treatments (Doxo and TMZ, as suggested by triple negative cells that are TMZ-resistant and fails to activate CMA). The LAMP-2A expression level was specific for different cell lines and patient-derived tumour subtypes, and was also useful in discriminating patients for their survival rates. Moreover, molecular silencing or pharmacological blockage of HIF-1α activity reverted BC resistance to TMZ. The combination of low-dose Doxo with TMZ or PX-478 showed that the drug associations have synergistic behaviours. Conclusion Here, we demonstrated that CMA activity exerts a fundamental role in the responsiveness to different treatments, and LAMP-2A can be proposed as a reliable prognostic biomarker in breast cancer. In this context, HIF-1α, a potential target of CMA, can also be assessed as a valuable therapeutic target in BC in view of identifying new, more efficient and less toxic therapeutic drug combinations. Moreover, the possibility to combine Doxo with other drugs acting on different but coherent molecular targets could help overcome resistance and open the way to a decrease in the dose of the single drugs.

Background Breast cancer has been a disease in which treatment strategy has changed over time under the influence of different hypotheses and evidence for more than a century. We analyzed the contribution of radiotherapy to disease-free survival and overall survival by classifying according to stage, 1–3 lymph node involvement, and molecular subgroups. Methods Following the approval of the Institutional Review Board, records of patients with breast cancer who were admitted to University School of Medicine Departments of Radiation Oncology and Medical Oncology between July 1999 and December 2020 were reviewed. Using data propensity score matching was performed between the groups that did and did not receive radiotherapy using an optimal matching algorithm (optimum, 1:1). Disease-free survival and overall survival after propensity score matching were calculated using the Kaplan-Meier method. Univariate and multivariate Cox regression analysis was used to estimate hazard ratios. Results In the radiotherapy and non-radiotherapy groups, disease-free survival was 257.42 ± 5.46 (246.72- 268.13), 208,96 ± 8,15 (192,97–224,94) months respectively, ( p = < 0.001) , overall survival was 272,46 ± 8,68 (255,43–289,49), 219,05 ± 7,32 (204,70–233,41) months respectively ( p  = .002). We compared the 19 N1 patient groups who received radiotherapy with the 19 patients who did not receive radiotherapy and calculated the disease-free survival times was 202,21 ± 10,50 (181,62–222,79) and 148,82 ± 24,91 (99,99–197,65) months respectively ( p  = .011) and overall survival times was 200,85 ± 12,79 (175,77–225,92) and 166,90 ± 20,39 (126,93–206,82) months respectively ( p  = .055). We examined disease-free survival and overall survival times in both groups according to Luminal A, Luminal B, TNBC, and HER2-enriched subgroups. In the Luminal B subgroup, the disease-free survival duration in the groups receiving radiotherapy and not receiving radiotherapy was 264.83 ± 4.95 (255.13-274.54) and 187.09 ± 11.06 (165.41-208.78) months ( p  < .001), and overall survival times were 252.29 ± 10.54 (231.62-272.97) and 197.74 ± 9.72 (178.69–216.80) months ( p  = .001) respectively. Conclusions Thanks to studies proving that RT increases long-term survival rates in breast cancer as a result of reducing locoregional recurrence and systemic metastasis rates, it has been understood that the spectrum hypothesis is the hypothesis that most accurately describes breast cancer to date. We found that patients with Luminal B invasive breast cancer benefited significantly more from RT compared to other subgroups.

The luminal B molecular subtype of breast cancers (BC) accounts for more than a third of BCs and is associated with aggressive clinical behavior and poor prognosis. The use of endocrine therapy in BC treatment has significantly contributed to the decrease in the number of deaths in recent years. However, most BC patients with prolonged exposure to estrogen receptor (ER) selective modulators such as tamoxifen develop resistance and become non-responsive over time. Recent studies have implicated overexpression of the ZNF703 gene in BC resistance to endocrine drugs, thereby highlighting ZNF703 inhibition as an attractive modality in BC treatment, especially luminal B BCs. However, there is no known inhibitor of ZNF703 due to its nuclear association and non-enzymatic activity. Here, we have developed an antisense oligonucleotide (ASO) against ZNF703 mRNA and shown that it downregulates ZNF703 protein expression. ZNF703 inhibition decreased cell proliferation and induced apoptosis. Combined with cisplatin, the anti-cancer effects of ZNF703-ASO9 were improved. Moreover, our work shows that ASO technology may be used to increase the number of targetable cancer genes.

Dalpiciclib, a cyclin‐dependent kinase 4/6 (CDK4/6) inhibitor, has demonstrated significant clinical activity and manageable safety in advanced luminal breast cancer, yet its neoadjuvant value remains unestablished. The single‐arm, phase II DANCER trial (NCT05640778) is the first to evaluate circulating tumor DNA (ctDNA)‐guided neoadjuvant CDK4/6 inhibitor therapy in patients with operable human epidermal growth factor receptor 2 (HER2)‐negative luminal B breast cancer, a subtype with poor chemotherapy response and unmet neoadjuvant needs. Thirty patients received dalpiciclib plus aromatase inhibitors (DAL‐AI) with ctDNA monitoring and multiomics profiling. At week 2, 26 (86.7%) patients achieved complete cell cycle arrest (primary endpoint). By surgery, 60.0% had partial response; breast pathological complete response and residual cancer burden 0–I rates were 6.7 and 3.3%, respectively. Treatment was well tolerated, with the most common grade ≥3 adverse events being neutropenia and leukopenia. Candidate predictive biomarkers included ctDNA clearance, GSTM1 copy number, MammaPrint index, plasma CCL4/CCL19 levels, and tissue pRb/CDK4 expression. A novel baseline response index combining CCL4 and pRb showed excellent predictive performance and stratified patients by likelihood of clinical benefit, with ctDNA dynamics further refining stratification. These findings support DAL‐AI as a promising neoadjuvant option and highlight the value of biomarker‐guided strategies for treatment optimization. DANCER (NCT05640778) was a circulating tumor DNA (ctDNA)‐directed, single‐arm, phase II trial investigating the clinical activity of dalpiciclib combined with aromatase inhibitors as a neoadjuvant regimen for operable human epidermal growth factor receptor 2 (HER2)‐negative luminal B breast cancer. Although a high complete cell cycle arrest (CCCA) rate (primary endpoint) of 86.7% (26 out of 30) was achieved at 2 weeks, some patients showed suboptimal clinical responses after neoadjuvant therapy. Comprehensive multiomics biomarker analysis revealed that patients with early ctDNA clearance, MammaPrint low‐risk status, GSTM1 deletion, increased tissue pRb/CDK4 expression, and higher plasma CCL4/CCL19 levels are likely to benefit more from neoadjuvant dalpiciclib therapy. The lower right (BIOMARKERS) panel was created in BioRender. Zhou, Y. (2025) https://BioRender.com/ax0bxdu.

Background Luminal B cancers show much worse outcomes compared to luminal A. This present study aims to screen key lncRNAs and mRNAs correlated with luminal-B breast cancer. Methods Luminal-B breast cancer tissue samples and adjacent tissue samples were obtained from 4 patients with luminal-B breast cancer. To obtain differentially expressed mRNAs (DEmRNAs) and lncRNAs (DElncRNAs) between luminal-B breast cancer tumor tissues and adjacent tissues, RNA-sequencing and bioinformatics analysis were performed. Functional annotation of DEmRNAs and protein-protein interaction networks (PPI) construction were performed. DEmRNAs transcribed within a 100 kb window up- or down-stream of DElncRNAs were searched, which were defined as cis nearby-targeted DEmRNAs of DElncRNAs. DElncRNA-DEmRNA co-expression networks were performed. The mRNA and lncRNA expression profiles were downloaded from The Cancer Genome Atlas (TCGA) database to validate the expression patterns of selected DEmRNAs and DElncRNAs. Results A total of 1178 DEmRNAs and 273 DElncRNAs between luminal-B breast cancer tumor tissues and adjacent tissues were obtained. Hematopoietic cell lineage, Cytokine-cytokine receptor interaction, Cell adhesion molecules (CAMs) and Primary immunodeficiency were significantly enriched KEGG pathways in luminal-B breast cancer. FN1, EGFR, JAK3, TUBB3 and PTPRC were five hub proteins of the PPI networks. A total of 99 DElncRNAs-nearby-targeted DEmRNA pairs and 1878 DElncRNA-DEmRNA co-expression pairs were obtained. Gene expression results validated in TCGA database were consistent with our RNA-sequencing results, generally. Conclusion This study determined key genes and lncRNAs involved in luminal-B breast cancer, which expected to present a new avenue for the diagnosis and treatment of luminal-B breast cancer.