Chemotherapy resistance in breast cancer: new factors identified
In various types of cancer, many tumors are resistant to cancer treatment. For example, in luminal breast cancers (the most common type of breast cancer), a major problem is resistance to chemotherapy. This resistance involves regulation of expression of many genes. To better understand this phenomenon, Martin Dutertre, Inserm researcher in the Biology of the RNA, Signaling and Cancer team led by Stéphan Vagner (Inserm U1278 and UMR 3348 CNRS), along with Iris Tanaka (PhD student at the University of Paris Saclay), have studied the role of gene regulation in alternative splicing.
Alternate splicing of transcripts allows most human genes to code for several different proteins. A phenomenon that we have been aware of for more than a decade that plays a role in cancer, but whose role in resistance to treatment was little explored.
Splicing networks control the resistance
Utilizing an in vitro cellular model of doxorubicin resistance in luminal breast cancers, the team studied alternative splicing across the genome using RNA-seq. "Some studies have found that a gene with alternative splicing modified in resistance. But they were always isolated. This time, the study is pan-genome and mechanistic." As a result, scientists have pinpointed more than 1,700 alternative spikes associated with resistance. Better yet, the team found two splicing factors, called ZRANB2 and SYF2, which each control about 100 alternative splicings, and which control the resistance.
Alternative splicing as markers of resistance to chemotherapy
The team was particularly interested in an alternative splicing located in the ECT2 gene and controlled by both ZRANB2 and SYF2. In vitro and in vivo analyses (the latter in the Translational Research Department of Institut Curie) indicate that ECT2 alternative splicing plays a role in doxorubicin resistance. In addition, analysis of a large collection of breast cancers, in collaboration with Ivan Bièche (Pharmacogenomics unit, Genetics Department of Institut Curie) has shown that this alternative splicing is associated with poor prognosis, specifically in the luminal type and in patients treated with chemotherapy with epirubicin (doxorubicin).
This work, published in the Nucleic Acids Research journal, opens up new perspectives. On the one hand, concerning the biological role of the factors identified and their potential interest in other cancers:
These factors appear to control the ability of cells to slow down their DNA replication in the presence of stress, yet a similar phenomenon has been observed in cancer stem cells, which are resistant to chemotherapy.
On the other hand, the systematic study of alternative splicing in treatment-resistant tumors should aid in understanding the gene networks involved and identifying markers of resistance, and potentially, new therapeutic targets. Martin Dutertre started this type of analysis (conducted at Institut Curie) on a collection of chemotherapy-resistant breast tumors.