Women-specific mechanisms may contribute to tumor progression

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Transformation of breast tumor cells in breast cancer. Crédits / Inserm &

Transformation of breast tumor cells in breast cancer. Crédits / Inserm – Xavier Coumoul

Researchers have demonstrated the role of a non-coding RNA [1] in the development of aggressive tumors, particularly in breast cancer. The study, conducted in collaboration between the Institut Curie, Inserm, CNRS, Institut Paoli Calmettes and Aix-Marseille University [2], has just been published in the journal Cell . These results could explain more broadly gender biases in the presentation of certain pathologies.

All mammals have two sex chromosomes. Female mammals have two X chromosomes, unlike males who have one X and one Y chromosome. The role of a specific non-coding RNA, called XIST, in initiating the inactivation of one of the two X chromosomes of the female was already known. The purpose of this inactivation is to block the double expression of genes located on this chromosome because it affects the viability of the cells. In this new study, scientists show that XIST not only plays a role in triggering this inactivation of the X chromosome but also in maintaining it throughout the life of the cells.

To achieve this result, the researchers studied the effects of XIST deletion in vivo. Several techniques were used for this purpose. Either we used genetic tools to block the expression of XIST, or we used CRISPR [ 3] techniques to interfere with the expression and we silenced the XIST gene,

The loss of XIST in the cell lines studied [4] has a significant effect on the homoeostasis [5] of the breast tissue and impacts tumour development. Raphaël Margueron points out that when tumors are studied and the properties of these tumors are examined afterwards, there is a tendency for XIST to be absent from the most aggressive breast tumors. As well as a reactivation of a certain number of inactive X genes.

Some reactivated genes and the transcript goes into overdrive

Among the genes reactivated by the loss of XIST, the researchers identified the gene coding for MED14, an essential subunit within the Médiator protein complex. It plays a role in the control of gene expression.

In conclusion, the loss of XIST leads to the reactivation of certain genes (on the inactive X chromosome) involved in cell differentiation and impacts the development of aggressive tumor cells. As this pattern is specific to the presence of two X chromosomes, these results will play a major role in the study of gender-related pathologies.

This study suggests that the expression of XIST as well as certain genes linked to the X chromosome could be used as markers for the development of new therapeutic strategies,

Focus: Transcription initiation

The expression of genes is controlled by promoters but also by pieces of DNA, which can be quite distant from the gene and the promoter, called enhancers. There is communication between the enhancers and the promoters. The Médiator complex intervenes in this communication and allows the enhancers to finely regulate the expression of the genes. explains Raphaël Margueron.

[1] Pigmentation is a discipline that studies the mechanisms involved in the regulation of genes, which is essential for the action of cells and the maintenance of their identity.

[2] The work was carried out in the research unit of genetics and biology of development (Institut Curie, CNRS, Inserm, Sorbonne University) by the Molecular Biology team;development (Institut Curie, CNRS, Inserm, Sorbonne University) by Raphael Margueron’s Polycomb Protein Pressure Mechanism team; at the Cancer Research Center of Marseille (CRCM / Inserm, CNRS, Aix-Marseille University, Centre de Lutte Contre le Cancer de la région PACA-Institut Paoli-Calmettes) by Emmanuelle Charaffe-Jauffret and Christophe Ginestier’s team and with the EMBL Heidelberg (Edith Heard)

[3] The CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technique consists of interrupting or suspending the expression of a gene by targeting it in a precise manner.

[4] The breast tissue contains ducts composed of basal and luminal cells. The chosen cell lines allow to reproduce this tissue homogeneity.

[5] Maintenance of the balance between the internal and external environment.

[6] Differentiation is the ability of a cell to acquire its own function. A stem cell can become any cell (muscular, excretory, bone, etc.) but it is its location (thus its environment and the transcription factors found there) that will determine its fate.

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