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    A. Magklara Laboratory

    Research Directions

    The group's main interests lie in the field of medical epigenetics. We seek to understand the contribution of epigenetic factors (DNA methylation, histone modifications, microRNAs) in the pathogenesis of human disease focusing on cancer. By applying genome-wide approaches to study gene regulation and chromatin dynamics we are currently investigating the role of epigenetic mechanisms in breast cancer. Our ultimate goal is to identify deregulated epigenetic pathways that can be targeted for therapeutic purposes. At present, there are two main projects underway in the lab as described below

    1. Study of the epigenome of breast cancer stem cells

    Funded by Marie Curie grant N° 303519- EPIGBRCASTEM (FP7-PEOPLE-2011-CIG)

    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 an increasing belief that cancer stem cells (CSCs) are, largely, accountable. A growing body of evidence suggests that CSCs have the ability of self-renewal and can support cancer progression, while the rest of the tumour cells have only limited proliferative capacity and do not significantly contribute to tumour growth.

    According to the cancer stem cell theory (Figure 1), the development of a tumour imitates that of normal tissue following a specific differentiation pattern (from stem cells to transient amplifying cells to terminally differentiated ones), a process likely to be epigenetically regulated. The most common epigenetic mechanisms are DNA methylation, post-translational histone modifications and small non-coding RNAs. These mechanisms affect gene expression without altering the underlying DNA sequence and can be inherited through cell division. Their important role in the genesis and progression of several types of cancer, including breast cancer, is well established. Since epigenetic changes are potentially reversible, much effort has been directed, in recent years, to finding novel therapies that could restore the normal epigenetic landscape. However, epigenetic treatments for breast cancer, currently under evaluation, target the phenotypic characteristics of the bulk of the tumour (Figure 2), and not those of the CSCs. There is little data about the epigenome of breast CSCs and how this evolves during differentiation. Evidently, to develop effective, epigenetic treatments that aim to eradicate the tumorigenic CSCs, we need to reveal first the unique epigenetic traits that allow them their proliferative and tumorigenic capacity. To this end we are currently working on the isolation of breast CSCs and the characterization of their epigenetic landscape through the application of next-generation sequencing.

    2. Epigenetics of progesterone receptor signaling in breast cancer

    Progesterone is a steroid hormone that plays a pivotal role in female physiology. It is a key regulator of the reproductive system (uterus and ovaries) and of mammary gland morphogenesis, while it has lesser effects in other tissues including the brain and the thymus. It exerts its actions through its cognate receptor, the progesterone receptor (PR), a ligand-activated transcription factor. Progesterone signaling is also implicated in the development and progression of cancer in the hormone's target tissues. In breast cancer the role of PR is well documented both in vivo and in vitro. Experiments in PR knock-out mice demonstrated that progestins promote mammary tumor progression and growth. Large clinical studies in women have also provided supporting evidence for a tumorigenic role of progesterone in the breast. In vitro studies have confirmed that progestin treatment affects important cellular programs, such as proliferation, apoptosis and differentiation, all of which have the potential to lead to a malignant phenotype when deregulated. The epigenetic mechanisms that mediate PR's effects on these biological processes are not fully deciphered yet.

    We have employed next-generation sequencing (NGS) to interrogate the transcriptome and the cistrome of vehicle- and progestin- treated breast cancer cells in an unbiased way. We are mostly interested in unraveling the epigenetic mechanisms induced by the progesterone receptor in breast cancer; therefore, regulatory sites of target genes are profiled for epigenetic modifications. Our aim is to identify the chromatin modifying enzymes involved in induction and repression or PR targets (Figure 3) and characterize their interplay with the receptor. Our ultimate goal is to identify epigenetic drugs that target these pathways and can be potentially used in the treatment of PR+ breast cancer.