A drug reveals its secrets
Published on October 3, 2018
The team of professor Sylvie Mader at IRIC just published a study, conducted by Dr. Tatiana Traboulsi and her colleagues, which explains the mechanism of action of certain anti-estrogen drugs such as fulvestrant, a drug clinically known as Faslodex. The results of this research were recently published in the journal Oncogene.
About 70% of breast cancers fall into the subgroup of “estrogen receptor positive” cancers. Cells of these cancers have a distinguishing feature: they proliferate under the action of the hormone estrogen.
Estrogen acts by entering the cells and then binding the ERα receptors (Estrogen Receptor alpha). This association modifies the receptors and activates them. The activated receptors then attach to the DNA, and stimulate a series of genes that eventually lead the cell to multiply.
Drugs belonging to the group of anti-estrogens prevent this action by binding the ERα receptors themselves. However, it was not yet clear how some of these drugs, such as fulvestrant, currently used for the treatment of metastatic breast tumors, exerted their action. This is what Sylvie Mader’s team helped clarify.
By conducting a series of experiments in cultured cells, IRIC researchers followed step by step the effect of pure anti-estrogens, such as fulvestrant, on the estrogen receptor.
They demonstrated that the receptors, once bound by the drug, undergo a transformation called “sumoylation”. As a result, these receptors bind only transiently (20 to 40 minutes) to the DNA, which is then compacted, preventing the pro-cancer genes from being activated.
The researchers tested their model by studying also a type of ERα receptor resistant to hormonal therapies. They showed that in the presence of fulvestrant, it did not undergo sumoylation. Moreover, it remained associated with DNA for a longer period and partially induced genes that estrogen normally stimulates.
This work provides a better understanding of how certain drugs used to treat breast cancer work and of the mechanisms of resistance to these treatments. It provides important information for the optimization of these molecules and their use in the clinic.
By Martin Primeau
Role of SUMOylation in differential ERα transcriptional repression by tamoxifen and fulvestrant in breast cancer cells
Traboulsi T, El Ezzy M, Dumeaux V, Audemard E, Mader S
Oncogene, September 6, 2018