Breast cancer remains the second most common cause of death from cancer in women, despite progress in both diagnosis and treatment. The highly heterogeneous nature of the disease is a major obstacle to its successful treatment, leading to the development of drug resistance and, ultimately, to relapse in a significant number of patients. In recent years, more and more research studies have supported the view that cancer stem cells (CBCs) may contribute, at least in part, to these particularly malignant characteristics of the disease. CBCs are a small cellular subpopulation of the tumor, they have the ability to self-renew, but also to differentiate towards other cancer cells, while they exhibit particular resistance to conventional anti-cancer therapies. Due to these properties, CBC are considered to be involved in tumour growth and metastasis and are responsible for the recurrence of the disease after treatment. Therefore, breast CBCs are ideal candidates for the development of new, targeted therapies, which, in combination with conventional treatment regimens, may be more effective in treating the disease. First, however, an in-depth understanding of the specific characteristics of CBC and how they contribute to breast cancer is required.Epigenetic mechanisms, such as DNA methylation and post-translation modifications of histones, control gene expression and play a primary role in vital, physiological functions of the cell. Numerous studies, over the last decade, have shown that deregulation of these mechanisms contributes to the development and development of cancer. They seem to play a particularly important role in CBC biology, where they are responsible for regulating their unique characteristics, such as self-renewal. Since epigenetic modifications are potentially reversible, efforts have been made in recent years to find new therapies that can restore the normal epigenetic “land” in cancer cells, ultimately aspiring to restore the normal expression of genes that are epigenetically regulated. Given that there is little information on the epigenetic mechanisms governing breast cancer heterogeneity, this research proposal aims to investigate the role of histone methylation in breast CBC biology. The focus of the study is LSD1/KDM1A (Lysine Specific demethylase 1). The main physiological role of LSD1 is to regulate the multivalence of embryonic stem cells. An increase in enzyme expression levels, however, is a key feature of oncogenesis, as it occurs in many different tumour types and is associated with poor prognosis and recurrence of the disease. Particularly interesting is that recent data involve LSD1 and cancer stem cell biology. As very little is known about its role in breast CBCs, the present proposal aims, in particular, to study the regulation of stem properties and the volumeogenicity of these cells by LSD1. The ultimate objectives are the clarification of the molecular mechanisms involved, as well as the evaluation of the enzyme as a possible therapeutic target in breast CBCs.For this purpose, in vitro experiments will be carried out in a well characterised breast CBC system and in vivo experiments with xenografts in rats. At the same time, cutting-edge technologies, such as the CRISPR-Cas9 system and next generation sequencing, will be used to decipher the role of LSD1 in breast CBCs.
