Using human breast cancer cells and the protein that causes fireflies to glow, a Johns Hopkins team has shed light on why some breast cancer cells become resistant to the anticancer effects of the drug tamoxifen. The key is a discovery of two genetic “dimmer switches” that apparently control how a breast cancer gene responds to the female hormone estrogen.
In a report published online July 7 by Human Molecular Genetics, the scientists show how a gene known as RET in breast cancer cells responds to estrogen by dialing up the manufacture of a signaling protein that instructs cells to divide and causes tumors to become aggressive through the escape from estrogen dependence.
Scientists have long known that breast cancers are either estrogen-receptor positive or estrogen-receptor negative. The positive subset, generally associated with better outcomes for patients, is sensitive to the drug tamoxifen, which blunts aggressive tumor growth through estrogen receptor inhibition, according to Zachary E. Stine, the research team’s lead author and a postdoctoral fellow working in the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
Used for decades to prevent and treat breast tumors that kill about 40,000 women a year, tamoxifen works on some types of breast cancers by interfering with the activity of estrogen. However, resistance to the drug frequently develops over time, and previous experiments by other laboratories have shown that RET plays some role in either altering resistance or maintaining it.
Thus, the Hopkins scientists focused on RET, searching for pieces of DNA in the vicinity of that gene that had the potential, when combined with estrogen, to act as switches controlling the amount of protein product RET manufactures.
After identifying 10 sites in the RET locus that bind with estrogen receptor alpha, the investigators cloned the DNA sequences in those areas, then attached to each a piece of genetic material responsible for producing luciferase, an enzyme that causes the luminescent glow of a firefly. This lab product was then put inside human breast cancer cells in a dish and exposed to estrogen. Two of the 10 sequences lit up much more brightly than the others, revealing increased activity by the RET gene in response to estrogen.
“Those two sequences clearly are genetic hubs for the dialing up and dialing down of RET activity in response to estrogen,” says Andrew McCallion, Ph.D., an associate professor in the McKusick-Nathans Institute of Genetic Medicine, and corresponding author on the study.
In a second experiment, the team used the cloned sequence and luciferase concoction, inserted it into a breast cancer gene, and this time added retinoic acid instead of estrogen. Retinoic acid is well known to slow cancer cell growth. The scientists showed that one of the two sequences previously shown to be estrogen responsive also responded to retinoic acid and increased RET activity.
The investigators also found that when they put estrogen and retinoic acid together in breast cancer cells in culture, the increased activity of RET was much greater compared to either estrogen or retinoic acid alone.
Because it appears that increased RET activity is linked to more aggressive and tamoxifen-resistant types of breast cancers, the discovery is potentially important for making decisions about tamoxifen use, McCallion says. Understanding the genetics of these proteins also has the potential to guide the search for new therapeutic targets in breast cancer. With the new information, he says, steps might be taken to “resensitize” tumors that become tamoxifin- insensitive by manipulating the regulators of RET and, therefore, its protein products.
Support for this research came from the National Institutes of Health.
Authors of the paper, in addition to Stine and McCallion, are David M. McGaughey, Seneca L. Bessling and Shengchao Li, all of Johns Hopkins.On the Web:
Human Molecular Genetics: http://hmg.oxfordjournals.org/
Maryalice Yakutchik | Newswise Science News
Further reports about: > DNA > DNA sequence > Estrogen > Genetic Medicine > Genetic clues > Genetics > Human Molecular Genetics > Molecular Target > RET > breast cancer > breast cancer cells > cancer cells > cancer gene > discover > estrogen receptor > human breast cancer > human breast cancer cells > retinoic acid > sensitivity
Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory
How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
24.03.2017 | Materials Sciences
24.03.2017 | Physics and Astronomy
24.03.2017 | Physics and Astronomy