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Breast cancer remains the most frequent cause of cancer death among women, both in developed and developing countries, despite advances in diagnosis and treatment. Major reasons of mortality are intrinsic and acquired resistance to endocrine therapy and disease relapse and there is increasingly solid evidence that cancer stem cells (CSCs) are, largely, accountable. CSCs constitute a subpopulation of tumor cells with unique characteristics, like the ability to self-renew and differentiate, and they are thought to sustain tumor growth. These features are believed to be regulated through epigenetic processes. Epigenetics refers to heritable changes in gene expression that do not involve changes in the underlying DNA sequence. Several epigenetic mechanisms exist with the most important ones being DNA methylation and post-translational histone modifications. There is little data about the epigenetic mechanisms functioning in breast CSCs (bCSCs) and we need to elucidate them in order to develop effective epigenetic treatments that target these cells. Furthermore, in the use of epigenetic drugs, it will be required to establish first in vitro systems, where the relevant protocols can be optimized.
Several recent studies have pinpointed to histone lysine demethylases as important players in the epigenetic control of cancer development and maintenance. This has spearheaded an effort to generate drugs that target these enzymes and several of them are currently in clinical trials. LSD1 is a histone demethylase that is involved in turning genes on as well as turning them off. It is involved in the maintenance of pluripotency of embryonic stem cells, while LSD1 overexpression is a common phenomenon in many different tumor types especially poorly differentiated ones, as well as in leukemic and hepatic cancer stem cells.
The main goal of this project was to set up an in vitro system, where we could study epigenetic mechanisms that regulate the fate of breast cancer stem cells and also test epigenetic drugs that may target them. Accordingly, we developed appropriate protocols for the isolation and culturing of breast cancer stem cells both from cell lines and from breast tumors. We extensively validated our system through FACS, RT-PCR and mammosphere formation assays, an in vitro surrogate of stemness. Subsequently, we undertook the task to investigate the role of LSD1 in bCSCs and evaluate its potential as a new drug target. Pharmacological inhibition of LSD1 led to diminished self-renewal capacity and a decrease in the CSC population. Experiments are underway to elucidate the gene networks that are under LSD1 regulation in bCSCs and to investigate the histone methylation alterations occurring in these cells.

Potential Impact: A new exciting area in cancer research is the study of cancer stem cells and the translational implications for possible epigenetic and/or differentiation therapies. Evidence of the effects of epigenetic modulating agents has revealed their dramatic consequences on cellular programming, in particular reversing stemness characteristics (e.g. self-renewal) and chemoresistance. Recent studies in AML showed that LSD1 keeps stem-cell subpopulations from properly leaving the self-renewal state, while LSD1 inhibition allows them to commit to cell lineages and differentiate. Our project explores the role of LSD1 in the maintenance of stem cell subpopulations in breast cancer. The results strongly suggest that LSD1 is important for the maintenance of the stem-like characteristics of bCSCs and contribute to the growing knowledge on the role of LSD1 in promoting tumorigenesis. Such findings will be of paramount importance in the introduction of new therapeutic strategies in the fight against breast cancer.

The present project was initially developed to support the move of a young researcher from the USA to the EE by providing funds to initiate her research and help her reintegration, while she awaited her academic appointment. By the end of the project, the Marie Curie Fellow has been fully integrated in the local academic community, as she has acquired the position of Assistant Professor and she has set up her research team as well as several national and international collaborations.