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Inflammatory breast cancer (IBC) is a rare yet aggressive breast cancer variant, associated with a poor prognosis. The major challenge for IBC is misdiagnosis due to the lack of molecular biomarkers. We profiled dysregulated expression of microRNAs (miRNAs) in primary samples of IBC and non-IBC tumors using human breast cancer miRNA PCR array. We discovered that 28 miRNAs were dysregulated (10 were upregulated, while 18 were underexpressed) in IBC vs. non-IBC tumors. We identified 128 hub genes, which are putative targets of the differentially expressed miRNAs and modulate important cancer biological processes. Furthermore, our qPCR analysis independently verified a significantly upregulated expression of miR-181b-5p, whereas a significant downregulation of miR-200b-3p, miR-200c-3p, and miR-203a-3p was detected in IBC tumors. Receiver operating characteristic (ROC) curves implied that the four miRNAs individually had a diagnostic accuracy in discriminating patients with IBC from non-IBC and that miR-203a-3p had the highest diagnostic value with an AUC of 0.821. Interestingly, a combination of miR-181b-5p, miR-200b-3p, and miR-200c-3p robustly improved the diagnostic accuracy, with an area under the curve (AUC) of 0.897. Intriguingly, qPCR revealed that the expression of zinc finger E box-binding homeobox 2 (ZEB2) mRNA, the putative target of miR-200b-3p, miR-200c-3p, and miR-203a-3p, was upregulated in IBC tumors. Overall, this study identified a set of miRNAs serving as potential biomarkers with diagnostic relevance for IBC.

In recent years, interest in personalized medicine has considerably increased [...]

Inflammatory breast cancer (IBC) is a rare, but aggressive entity of breast carcinoma with rapid dermal lymphatic invasion in young females. It is either poorly or misdiagnosed as mastitis because of the absence of a distinct lump. Small extracellular vesicles (sEVs) circulating in liquid biopsies are a novel class of minimally invasive diagnostic alternative to invasive tissue biopsies. They modulate cancer progression via shuttling their encapsulated cargo including microRNAs (miRNAs) into recipient cells to either trigger signaling or induce malignant transformation of targeted cells. Plasma sEVs < 200 nm were isolated using a modified cost-effective polyethylene glycol (PEG)-based precipitation method and compared to standard methods, namely ultracentrifugation and a commercial kit, where the successful isolation was verified by different approaches. We evaluated the expression levels of selected sEV-derived miR-181b-5p, miR-222-3p and let-7a-5p using quantitative real PCR (qPCR). Relative to non-IBC, our qPCR data showed that sEV-derived miR-181b-5p and miR-222-3p were significantly upregulated, whereas let-7a-5p was downregulated in IBC patients. Interestingly, receiver operating characteristic (ROC) curves analysis revealed that diagnostic accuracy of let-7a-5p alone was the highest for IBC with an area under curve (AUC) value of 0.9188, and when combined with miR-222-3p the AUC was improved to 0.973. Further, 38 hub genes were identified using bioinformatics analysis. Together, circulating sEV-derived miR-181b-5p, miR-222-3p and let-7a-5p serve as promising non-invasive diagnostic biomarkers for IBC.

Recent findings implicate the histone deacetylase (HDAC) inhibitor largazole as an inhibitor of Musashi RNA-binding protein function. Here, we assess this interplay and evaluate the relevance of largazole for triple-negative breast cancer (TNBC) progression and resistance to radiotherapy. Primary patient-derived TNBC cells and cell lines were treated with largazole and cell vitality, proliferation, motility, cell cycle, DNA synthesis as well as repair, and stemness were analyzed via MTT assay, digital holographic microscopy, and flow cytometry. To unravel the connection between largazole treatment and Musashi expression, miR-125b-5p was assessed after largazole treatment, and overexpressed as well as downregulated in TNBC wildtype cells to determine influence on Musashi levels. Targeted mRNA and protein expression analyses were complemented with RNA sequencing data after largazole treatment. Finally, DNA double strand breaks and post-radiogenic survival were quantified using γ-H2AX, 53BP1, and clonogenic assays. Largazole showed reduced metabolic activity in TNBC, but not in non-malignant cultures. Largazole treatment strongly abrogated proliferation, DNA synthesis, cell motility, and induced a cell cycle arrest. Levels of the Musashi proteins were downregulated after largazole treatment via upregulation of the miR-125b-5p. Protein expression and RNA sequencing analysis indicated a loss of cancer stemness-, cell cycle progression-, and DNA repair-associated signaling. Consequently, radiotherapy-induced DNA double strand breaks were increased while post-radiogenic cell survival was decreased in largazole-treated samples. The HDAC inhibitor largazole compromises tumor growth and motility and downregulates the Musashi proteins via the miR-125b-5p in TNBC. Additionally, largazole acts as a radiosensitizer by attenuating DNA repair, therefore supporting therapeutic efficacy.

The heparan sulfate proteoglycan syndecan-3 (SDC3) is a critical regulator of cell–matrix interactions. While other syndecan family members contribute to the progression of multiple cancers, SDC3’s functional contributions to tumor biology remain largely unexplored. This study investigates the potential role of SDC3 in the pathogenesis of breast cancer. By conducting an in-silico analysis of publicly available datasets, including TNM-plot, The Human Protein Atlas, and Kaplan–Meier Plotter, we observed that SDC3 is upregulated in breast cancer tissue. Notably, high SDC3 expression correlates with improved relapse-free survival in breast cancer patients. In vitro experiments revealed that SDC3 depletion significantly impairs cell viability, cell-cycle progression, cell migration, and 3D-spheroid-formation in MDA-MB-231 and MCF-7 breast cancer cells. Furthermore, SDC3 depletion results in dysregulated gene expression of matrix metalloproteinases (MMP1, MMP2, MMP9) in MDA-MB-231 cells, and upregulation of E-cadherin (CDH1) and vascular endothelial growth factor A (VEGFA) in MCF-7 cells. Activation of proto-oncogene tyrosine-protein kinase Src was inhibited when SDC3 depletion was combined with tissue factor pathway inhibitor treatment. These findings demonstrate that breast cancer cell-derived SDC3 plays a pivotal role in tumor progression.

Ferroptosis, an iron-dependent form of non-apoptotic cell death, plays a pivotal role in various diseases and is gaining considerable attention in the realm of endometriosis. Considering the classical pathomechanism theories, we hypothesized that ferroptosis, potentially driven by increased iron content at ectopic sites, may contribute to the progression of endometriosis. This retrospective case–control study provides a comprehensive immunohistochemical assessment of the expression and tissue distribution of established ferroptosis markers: GPX4, ACSL4, and TfR1 in endometriosis patients. The case group consisted of 38 women with laparoscopically and histologically confirmed endometriosis and the control group consisted of 18 women with other gynecological conditions. Our study revealed a significant downregulation of GPX4 in stromal cells of endometriosis patients (M = 59.7% ± 42.4 versus 90.0% ± 17.5 in the control group, t (54) = −2.90, p = 0.005). This finding aligned with slightly, but not significantly, higher iron levels detected in the blood of endometriosis patients, using hemoglobin as an indirect predictor (Hb 12.8 (12.2–13.5) g/dL versus 12.5 (12.2–13.4) g/dL in the control group; t (54) = −0.897, p = 0.374). Interestingly, there was no concurrent upregulation of TfR1 (M = 0.7 ± 1.2 versus 0.2 ± 0.4 for EM, t (54) = 2.552, p = 0.014), responsible for iron uptake into cells. Our empirical findings provide support for the involvement of ferroptosis in the context of endometriosis. However, variances in expression patterns within stromal and epithelial cellular subsets call for further in-depth investigations.

Breast cancer (BrC) is a major public health problem worldwide. The intra-tumoral heterogeneity and tumor cell plasticity importantly contribute to disease progression and treatment failure. However, the dynamic interactions between different tumor clones, as well as their contribution to tumor aggressiveness are still poorly understood. In this study, we provide evidence of a lateral transmission of aggressive features between aggressive and non-aggressive tumor cells, consisting of gain of expression of cancer stem cell markers, increased expression of CXCL12 receptors CXCR4 and CXCR7 and increased invasiveness in response to CXCL12, which correlated with high levels of secretion of pro-inflammatory mediators G-CSF, GM-CSF, MCP-1, IL-8 and metalloproteinases 1 and 2 by the aggressive cells. Noteworthy, we found no evidence of a TGF-β participation in the inducible-invasive phenotype. Altogether, our results provide evidence of communication between tumor cells with different potentials for aggressiveness, which could influence intra-tumoral population dynamics promoting the emergence of clones with novel functions. Understanding these interactions will provide better targets for diagnosis, prognosis and therapeutic strategies.

Inflammation is a well-known driver of carcinogenesis and cancer progression, often attributed to the tumor microenvironment. However, tumor cells themselves are capable of secreting a variety of inflammatory molecules, leading to the activation of specific signaling pathways that promote tumor progression. The NF-κB signaling pathway is one of the most important connections between inflammation and tumorigenesis. NF-κB is a superfamily of transcription factors that plays an important role in several types of hematological and solid tumors, including breast cancer. However, the role of the NF-κB pathway in the survival of breast cancer patients is poorly studied. In this study, we analyzed and related the expression of both canonical and alternative NF-κB pathways and selected target genes with the relapse-free and overall survival of breast cancer patients. We used the public database Kaplan-Meier plotter (KMplot) which includes gene expression data and survival information of 3951 breast cancer patients. We found that the expression of was associated with poor relapse-free survival in patients with ER-positive tumors. Moreover, the expression of and was associated with poor relapse-free and overall survival. In contrast, expression of , and from the canonical pathway, and and from the alternative pathway correlated with better relapse-free survival also when the patients were classified by their hormonal and nodal status. Our study suggests that the expression of genes of the canonical and alternative NF-κB pathways is ultimately critical for tumor persistence. Understanding the communication between both pathways would help to find better therapeutic and prophylactic targets to prevent breast cancer progression and relapse.

[This corrects the article on p. 205 in vol. 8, PMID: 28337194.].

In several carcinomas, the SET Domain Containing 3, Actin Histidine Methyltransferase (SETD3) is associated with oncogenesis. However, there is little knowledge about the role of SETD3 in the progression and prognosis of breast cancer. In this study, we first analyzed the prognostic value of SETD3 in breast cancer patients using the database of the public Kaplan-Meier plotter. Moreover, in vitro assays were performed to assess the role of SETD3 in the viability and capacity of invasion of human breast cancer cell lines. We observed that the high expression of SETD3 was associated with better relapse-free survival (RFS) of the whole collective of 3,951 patients, of Estrogen Receptor-positive, and of Luminal A-type breast cancer patients. However, in patients lacking expression of estrogen-, progesterone- and HER2-receptor, and those affected by a p53-mutation, SETD3 was associated with poor RFS. In vitro analysis showed that SETD3 siRNA depletion affects the viability of triple-negative cells as well as the cytoskeletal function and capacity of invasion of highly invasive MDA-MB-231 cells. Interestingly, SETD3 regulates the expression of other genes associated with cancer such as β-actin, FOXM1, FBXW7, Fascin, eNOS, and MMP-2. Our study suggests that SETD3 expression can act as a subtype-specific biomarker for breast cancer progression and prognosis.