Researchers characterise gene expression in endometrial cancer

A new study in eLife by researchers at Argentina’s ‘Consejo Nacional de Investigaciones Científicas y Técnicas’ (CONICET), together with specialists including Miguel Beato from the Center for Genomic Regulation of Barcelona (CRG), describe hormone-dependent gene expression in endometrial cancer and differentiate this in comparison to breast cancer.

"This is an important advance in understanding the tissue-specific mechanisms of steroid hormone action and the endocrine dysregulation of endometrial adenocarcinomas," says Patricia Saragüeta, CONICET researcher at the Institute of Biology and Experimental Medicine (IByME, CONICET) and leader of the project.

Progesterone and estradiol are ovarian hormones of steroid origin with traits that allow them to directly pass through membranes. "This means that they are in contact with receptors," explains Alejandro La Greca, a CONICET postdoctoral fellow at the Neuroscience Applied Research Laboratory (LIAN, Fleni-CONICET Institute). "The receptors for progesterone and estradiol receive these stimuli and then travel to the nucleus of the cell where they perform various functions, including those analyzed in the study as transcription factors." According to the researchers, the transcription factors are responsible for modifying the patterns of gene expression of the epithelium of the human endometrium.

There are other organs that share transcription factors and yet assume different functions in response to the same stimuli. What differentiates the endometrium from the breast? According to Saragüeta: “There are many factors that contribute to the complexity of the response, one of them being the three-dimensional organization of the two meters of DNA in the cell's genome, which is different in each type of tissue. Transcription factors access the information and the transcripts that will make the cell function in one way or another depending on this arrangement in space and time”.

In this sense, the study shows that "the topology of the DNA of the epithelial cells of the human endometrium does not depend on its interaction with the progesterone and estradiol receptors and that these exert their function by joining in pre-existing places to the hormonal stimulus", explains Saragüeta. And he adds: "They do it with the help of other transcription factors, not directly involved in transcription but in the approach and interaction of the enhancing regulatory elements and the promoters of the target genes."

In addition, the team carried out genomic analyses of endometrial cancer, in which they were able to corroborate that the malignancy of tumours increases as long as they lose the progesterone receptor and PAX2, factors related to genomic regulation. For Saragüeta and La Greca, this discovery supports the use of PAX2 levels as a diagnostic indicator. According to Saragüeta, this "suggests that maintaining progesterone receptor and PAX2 levels may be a therapeutic option in this type of tumour.”

The researchers used genomic methods that allowed them to analyse the three-dimensional configuration of the genome of a cell. Pioneers in using this methodology, La Greca highlights the collaboration with the Centre for Genomic Regulation of Barcelona to carry out sequencing. Led by Saragüeta, the team was able to observe all the regions of the genome that bind to the progesterone receptor. It was also possible to record which elements interact with the progesterone receptor in order to generate a coordinated regulation of the tissue. The participation of the group led by Nicolas Bellora, CONICET researcher at the Institute of Nuclear Technologies for Health (INTECNUS) in Bariloche, and by Elmer Fernandez, CONICET researcher at the Centre for Research and Development in Immunology and Infectious Diseases (CIDIE, CONICET-UCC ) from Córdoba, Argentina, was decisive for the bioinformatic analyses of the project.