Triple-negative breast cancer (TNBC) represents roughly one-sixth of all breast cancer patients, but accounts for 30–40% of breast cancer deaths. Due to the lack of typical biomarkers exploited clinically for breast cancer, it remains very difficult to treat. Moreover, its intrinsic high heterogeneity and proneness to become resistant to the drugs administered makes the treatment management very challenging for oncologists. Herein, we outline the different therapies used currently for TNBC and list the ongoing clinical trials to provide an overview of the most recent TNBC therapeutic landscape. In addition, we highlight the emerging therapies in the preclinical stage that hold the most promise, such as epigenetic modulators, CRISPR, miniproteins, radioconjugates, cancer vaccines, and PROTACs. Moreover, we navigate through the existing limitations and challenges which hamper the development of new and more effective treatments for TNBC. Lastly, we point to emerging new directions that may revolutionize future therapy for TNBC.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology has transformed oncology research in many ways. Breast cancer is the most prevalent malignancy globally and triple negative breast cancer (TNBC) is one of the most aggressive subtypes with numerous challenges still to be faced. In this work, we have explained what CRISPR consists of and listed its applications in breast cancer while focusing on TNBC research. These are disease modelling, the search for novel genes involved in tumour progression, sensitivity to drugs and immunotherapy response, tumour fitness, diagnosis, and treatment. Additionally, we have listed the current delivery methods employed for the delivery of CRISPR systems in vivo. Lastly, we have highlighted the limitations that CRISPR technology is subject to and the future directions that we envisage. Overall, we have provided a round summary of the aspects concerning CRISPR in breast cancer/TNBC research.

Breast cancer (BC) is the most diagnosed cancer worldwide and one of the main causes of cancer deaths. BC is a heterogeneous disease composed of different BC intrinsic subtypes such as triple-negative BC (TNBC), which is one of the most aggressive subtypes and which lacks a targeted therapy. Recent comprehensive analyses across cell types and cancer types have outlined a vast network of protein–protein associations between transcription factors (TFs). Not surprisingly, protein–protein networks central to oncogenesis and disease progression are highly altered during TNBC pathogenesis and are responsible for the activation of oncogenic programs, such as uncontrollable proliferation, epithelial-to-mesenchymal transition (EMT) and stemness. From the therapeutic viewpoint, inhibiting the interactions between TFs represents a very significant challenge, as the contact surfaces of TFs are relatively large and featureless. However, promising tools have emerged to offer a solution to the targeting problem. At the clinical level, some TF possess diagnostic and prognostic value in TNBC. In this review, we outline the recent advances in TFs relevant to TNBC growth and progression. Moreover, we highlight different targeting approaches to inhibit these TFs. Furthermore, the validity of such TFs as clinical biomarkers has been explored. Finally, we discuss how research is likely to evolve in the field.

The sensitivity of pleural fluid (PF) analyses for the diagnosis of malignant pleural effusions (MPEs) is low to moderate. Knowledge about the pathobiology and molecular characteristics of this condition is limited. In this study, the crosstalk between stromal cells and tumor cells was investigated in vitro in order to reveal factors that are present in PF which can mediate MPE formation and aid in discriminating between benign and malignant etiologies. Eighteen PF samples, in different proportions, were exposed in vitro to mesothelial MeT-5A cells to determine the biological effects on these cells. Treatment of normal mesothelial MeT-5A cells with malignant PF increased cell viability, proliferation, and migration, and activated different survival-related signaling pathways. We identified differentially expressed miRNAs in PF samples that could be responsible for these changes. Consistently, bioinformatics analysis revealed an enrichment of the discovered miRNAs in migration-related processes. Notably, the abundance of three miRNAs (miR-141-3p, miR-203a-3, and miR-200c-3p) correctly classified MPEs with false-negative cytological examination results, indicating the potential of these molecules for improving diagnosis. Malignant PF produces phenotypic and functional changes in normal mesothelial cells. These changes are partly mediated by certain miRNAs, which, in turn, could serve to differentiate malignant from benign effusions.

We have established a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify novel genes playing a role in epigenetic regulation in mammals. We hypothesize that the ENU mutagenesis screen will lead to the discovery of unknown genes responsible of the maintenance of the epigenetic state as the genes found are modifiers of variegation of the transgene green fluorescent protein (GFP) expression in erythrocytes, which are named MommeD. Here we report the generation of a novel mutant mouse line, MommeD46, that carries a new missense mutation producing an amino acid transversion (L71P) in the dimerization domain of Nuclear Respiratory Factor 1 (Nrf1). The molecular characterization of the mutation reveals a decrease in the Nrf1 mRNA levels and a novel role of Nrf1 in the maintenance of the DNA hypomethylation in vivo. The heritability of the mutation is consistent with paternal imprinting and haploinsufficiency. Homozygous mutants display embryonic lethality at 14.5 days post-coitum and developmental delay. This work adds a new epi-regulatory role to Nrf1 and uncovers unknown phenotypical defects of the Nrf1 hypomorph. The generated mouse line represents a valuable resource for studying NRF1-related diseases.