P63, a member of the p53 protein family, plays key roles in epithelial development and carcinogenesis. In breast cancer, p63 expression has been found predominantly in basal-A (epithelial-type) triple-negative breast carcinomas (TNBC). To investigate the functional role of p63 in basal-A TNBC, we created MDA-MB-468 cell lines with inducible expression of the two major N-terminal p63 isoforms, TAp63α and ∆Np63α. TAp63α did not have significant effect on gene expression profile and cell phenotype, whilst the main effect of ΔNp63α was reduction of cell adhesion. Gene expression profiling revealed genes involved in cell adhesion and migration whose expression relies on overexpression of ΔNp63α. Reduced cell adhesion also led to decreased cell proliferation in vitro and in vivo. Similar data were obtained in another basal-A cell line, BT-20, but not in BT-549 basal-B (mesenchymal-like) TNBC cells. In basal-A TNBC cells, ∆Np63α has much stronger effects on gene expression than TAp63α. Although p63 is mentioned mostly in connection with breast cell differentiation and stem cell regulation, we showed that a major effect of p63 is regulation of cell adhesion, a process important in metastasis and invasion of tumour cells. That this effect is not seen in mesenchymal-type TNBC cells suggests lineage-dependent functions, mirroring the expression of ∆Np63α in primary human breast cancers.

Cancer cells have a remarkable ability to evade recognition and destruction by the immune system. At the same time, cancer has been associated with chronic inflammation, while certain autoimmune diseases predispose to the development of neoplasia. Although cancer immunotherapy has revolutionized antitumor treatment, immune-related toxicities and adverse events detract from the clinical utility of even the most advanced drugs, especially in patients with both, metastatic cancer and pre-existing autoimmune diseases. Here, the combination of multi-omics, data-driven computational approaches with the application of network concepts enables in-depth analyses of the dynamic links between cancer, autoimmune diseases, and drugs. In this review, we focus on molecular and epigenetic metastasis-related processes within cancer cells and the immune microenvironment. With melanoma as a model, we uncover vulnerabilities for drug development to control cancer progression and immune responses. Thereby, drug repurposing allows taking advantage of existing safety profiles and established pharmacokinetic properties of approved agents. These procedures promise faster access and optimal management for cancer treatment. Together, these approaches provide new disease-based and data-driven opportunities for the prediction and application of targeted and clinically used drugs at the interface of immune-mediated diseases and cancer towards next-generation immunotherapies.