A new study from The Scripps Research Institute (TSRI), in which two researchers from Baylor College of Medicine in Houston participated, found new targets for potential intervention in breast cancer. The targets could increase the effectiveness of the current treatments and reduce the side effects associated. The study, “Influence of Domain Interactions on Conformational Mobility of the Progesterone Receptor as Detected by Hydrogen/Deuterium Exchange Mass Spectrometry” was recently published at the journal Structure.
According to the line of research followed by the investigators, breast cancer is motivated by receptors that bind the hormone estrogen in approximately two out of every three cases and enable the cancer cells to grow when bonded to the receptors in cancer cells. The progesterone receptor has two activation domains, AF1 and AF2, which are normally both needed to activate the receptor completely. The study was able to determine how both domains work together.
“Using hydrogen-deuterium exchange technology, our study pinpoints just how AF2 communicates with AF1—the first evidence of the long-range interaction between these two functional domains,” said Patrick R. Griffin, a TSRI professor who led the study. “These findings support further research to look for promising small molecules that block that interaction.”
Using this methodology, the investigators were able to identify the structural changes that occur as a result of the interaction and to determine the conformational flexibility of intact multi domain proteins. These findings have additional significance since in some mutations the AF2 domain is deleted, but it still drives cancer trough the AF1 domain.
“Many features of the androgen receptor are similar to progesterone receptor, as they belong to the same subfamily of steroid receptors,” said Devrishi Goswami, co -author of the study and a member of the Griffin laboratory. “It could work the very same way. So these new insights may also help in finding new approaches to treating hormone-therapy-resistant prostate cancer.”
The drugs currently used for the treatment of these types of cancers target only the AF2 domain, since the AF1 is dynamic and frequently changes shape, which makes it harder to be targeted with drugs. However, researchers believe these findings will enable the study of new drugs for breast cancer, and as well for prostate cancer, which is also a hormone-driven disease.
In addition to the authors Goswami and Griffin, and Baylor College of Medicine researchers Celetta Callaway and Dean P. Edwards, Raj Kumar of The Commonwealth Medical College, Scranton, Pennsylvania also participated in the study. The study was funded by The National Institutes of Health and the National Cancer Institute.