RESUMEN
Gap junctions, membrane-based channels comprised of connexin proteins (Cxs), facilitate direct communication among neighbouring cells and between cells and the extracellular space through their hemichannels. The normal human breast expresses various Cxs family proteins, such as Cx43, Cx30, Cx32, Cx46, and Cx26, crucial for proper tissue development and function. These proteins play a significant role in breast cancer development, progression, and therapy response. In primary tumours, there is often a reduction and cytoplasmic mislocalization of Cx43 and Cx26, while metastatic lesions show an upregulation of these and other Cxs. Although existing research predominantly supports the tumour-suppressing role of Cxs in primary carcinomas through channel-dependent and independent functions, controversies persist regarding their involvement in the metastatic process. This review aims to provide an updated perspective on Cxs in human breast cancer, with a specific focus on intrinsic subtypes due to the heterogeneous nature of this disease. Additionally, the manuscript will explore the role of Cxs in immune interactions and novel forms of intercellular communication, such as tunneling nanotubes and extracellular vesicles, within the breast tumour context and tumour microenvironment. Recent findings suggest that Cxs hold potential as therapeutic targets for mitigating metastasis and drug resistance. Furthermore, they may serve as novel biomarkers for cancer prognosis, offering promising avenues for future research and clinical applications.
Asunto(s)
Neoplasias de la Mama , Comunicación Celular , Conexinas , Humanos , Conexinas/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Femenino , Uniones Comunicantes/metabolismo , Microambiente Tumoral , Animales , Transducción de SeñalRESUMEN
Breast cancer is the most diagnosed cancer worldwide and represents the fifth cause of cancer mortality globally. It is a highly heterogeneous disease, that comprises various molecular subtypes, often diagnosed by immunohistochemistry. This technique is widely employed in basic, translational and pathological anatomy research, where it can support the oncological diagnosis, therapeutic decisions and biomarker discovery. Nevertheless, its evaluation is often qualitative, raising the need for accurate quantitation methodologies. We present the software BreastAnalyser, a valuable and reliable tool to automatically measure the area of 3,3'-diaminobenzidine tetrahydrocholoride (DAB)-brown-stained proteins detected by immunohistochemistry. BreastAnalyser also automatically counts cell nuclei and classifies them according to their DAB-brown-staining level. This is performed using sophisticated segmentation algorithms that consider intrinsic image variability and save image normalization time. BreastAnalyser has a clean, friendly and intuitive interface that allows to supervise the quantitations performed by the user, to annotate images and to unify the experts' criteria. BreastAnalyser was validated in representative human breast cancer immunohistochemistry images detecting various antigens. According to the automatic processing, the DAB-brown area was almost perfectly recognized, being the average difference between true and computer DAB-brown percentage lower than 0.7 points for all sets. The detection of nuclei allowed proper cell density relativization of the brown signal for comparison purposes between the different patients. BreastAnalyser obtained a score of 85.5 using the system usability scale questionnaire, which means that the tool is perceived as excellent by the experts. In the biomedical context, the connexin43 (Cx43) protein was found to be significantly downregulated in human core needle invasive breast cancer samples when compared to normal breast, with a trend to decrease as the subtype malignancy increased. Higher Cx43 protein levels were significantly associated to lower cancer recurrence risk in Oncotype DX-tested luminal B HER2- breast cancer tissues. BreastAnalyser and the annotated images are publically available https://citius.usc.es/transferencia/software/breastanalyser for research purposes.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/metabolismo , Conexina 43 , Recurrencia Local de Neoplasia , Programas Informáticos , Algoritmos , Procesamiento de Imagen Asistido por Computador/métodosRESUMEN
Connexins (Cxs) are integral membrane proteins that form high-conductance plasma membrane channels, allowing communication from cell to cell (via gap junctions) and from cells to the extracellular environment (via hemichannels). Initially described for their role in joining excitable cells (nerve and muscle), gap junctions (GJs) are found between virtually all cells in solid tissues and are essential for functional coordination by enabling the direct transfer of small signalling molecules, metabolites, ions, and electrical signals from cell to cell. Several studies have revealed diverse channel-independent functions of Cxs, which include the control of cell growth and tumourigenicity. Connexin43 (Cx43) is the most widespread Cx in the human body. The myriad roles of Cx43 and its implication in the development of disorders such as cancer, inflammation, osteoarthritis and Alzheimer's disease have given rise to many novel questions. Several RNA- and DNA-binding motifs were predicted in the Cx43 and Cx26 sequences using different computational methods. This review provides insights into new, ground-breaking functions of Cxs, highlighting important areas for future work such as transfer of genetic information through extracellular vesicles. We discuss the implication of potential RNA- and DNA-binding domains in the Cx43 and Cx26 sequences in the cellular communication and control of signalling pathways.