Spanning genetics , pharmacology and molecular biology, the researchers have identified a panel of thirteen genes associated with tumorous stem cells, which might be critical in the choice of treating patients with this subtype of breast cancer and whose high expression may be controlled by the use of inhibitors against the Bromo-and Extra-terminal Domains (BET) family of epigenetic readers. In the words of the UCLM researcher and coordinator of this project, Eva Galán, " the evaluation of this panel of genes in patients could forecast if they are going to respond to typical treatment or not".

In recent years, she added, the epigenetics machinery, which is responsible for modifying the expression of certain genes without modifying their sequence, has proved to " be crucial for maintaining the phenotype of tumorous stem cells, known as stemness. Specifically, the members of the BET family of epigenetic readers are becoming potential targets for treating cancer and they have already proved effective in preclinical trials for breast cancer". This encouraged the researchers to evaluate the effect of inhibitors of this family of epigenetic readers on the panel of identified genes and on stemness properties in triple negative breast cancer.

Using cell models and preclinical models in mice, the researchers observed that the JQ1 compound, a potential inhibitor of BET proteins, led to a fall in the gene expression of the thirteen identified genes. Moreover, this inhibitor distinctly altered the stemness properties in the in vitro cell models used. "This could lead to tumours that are less aggressive and more sensitive to standard treatment with chemotherapy, which will be reflected in a better prognosis for patients".

As stated by Doctor Ocana, director of the New Therapies Unit at the San Carlos Clinical Hospital, "it is important to identify new targets and genomic mechanisms associated with them" . Also, doctor Galán remarked that "if the patient shows a high expression of these biomarker genes, standard treatment may be evaluated alongside epigenetic inhibitors which help to reduce the expression in the whole panel, which could improve the therapeutic response of the patient" and points out that the results "show a promising step forward in the search for a more targeted and effective treatment against this disease".

Tumours are not made up of identical tumour cells in themselves. Specifically, triple negative breast cancer is enriched with a population of cells which share some characteristics with normal stem cells and which, therefore, are known as tumorous stem cells. These cells are, to a large extent, responsible for controlling the behaviour of the tumour, since they modulate the response to treatments and are capable of surviving most current pharmaceuticals. For this reason, identifying pharmaceuticals which can attack this population effectively is of vital importance.

The published work, presented at numerous national and international congresses, is part of a line of research for identifying new therapeutic vulnerabilities and developing combined therapies with the laboratory of Traslational Oncology, CRIB, of the UCLM and has been carried out in collaboration with the Albacete University Hospital Complex Research Unit (UI-CHUA), the San Carlos Clinical Hospital and the University of Semmelweis in Hungary.

Likewise, it has received funding from private entities, such as AMUMA (the Castilla-La Mancha Association of Breast and/or Gynaecological Cancer ) and ACEPAIN (Albacete Skin Stiches Association) and the CRIS CANCER Foundation (Madrid) as well as public entities such as the Albacete Provincial Government, the Castilla-La Mancha Regional Government, the Carlos III Institute of Health (ISCII) and the University of Castilla-La Mancha (UCLM).

The full article has been published in open access and can be consulted by clicking on the following link: https://link.springer.com/article/10.1007/s13402-020-00497-6

Gabinete de Comunicación UCLM. Albacete, 28th of April 2020