Navigation Links
Johns Hopkins researchers discover how some breast cancers alter their sensitivity to estrogen
Date:7/27/2011

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.


'/>"/>

Contact: Maryalice Yakutchik
myakutc1@jhmi.edu
443-287-2251
Johns Hopkins Medical Institutions
Source:Eurekalert

Related medicine news :

1. Jimmy Johnson Will Step Into Role as Honorary Crew Chief for ExtenZe Racing at Daytona
2. Protecting patients: Study shows that Johns Hopkins flu vaccination rates twice national average
3. Longtime Quality Assurance Executive Randy Johnson Joins White Pine Systems as Vice President of Product Services
4. Johns Hopkins scientists develop personalized blood tests for cancer using whole genome sequencing
5. AADR awards the 2010 Jack Hein Public Service Award to David C. Johnsen
6. Johnson & Johnson to Participate in RBC Capital Markets Health Care Conference
7. Robert Wood Johnson Foundation Launches New Scholars, Fellows & Leadership Programs Web Site
8. Johns Hopkins Launches “Energy Policy and Climate” Master's Degree
9. SC Johnson and Bill & Melinda Gates Foundation Unite to Combat Malaria
10. Johns Hopkins Health System Acquires Imorgon Ultrasound PACS Product
11. Cancer research award to Johns Hopkins basic scientist
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:10/13/2017)... ... October 13, 2017 , ... Southern ... and Jennifer Huggins, PharmD ’17, along with clinical associate professor Janice Frueh, ... cardiovascular diseases during the 15th Annual Women’s Health Conference. The SIU School ...
(Date:10/13/2017)... ... ... Apple Rehab Shelton Lakes , which specializes in the delivery of sub-acute ... of a disaster drill on October 3rd. , Apple Rehab participated with the Shelton ... well as the Connecticut Long Term Care Mutual Aid Plan (LTC-MAP). The LTC-MAP ...
(Date:10/13/2017)... N.J. (PRWEB) , ... October 13, 2017 , ... The ... Holly Day Market. Featuring a collection of specialty vendors and unique items from across ... personalized and quality-focused health and wellness services offered by the VNA. The boutique ...
(Date:10/13/2017)... NJ (PRWEB) , ... October 13, 2017 , ... Global ... at scenic Alexandria Park in Milford, NJ. This free event, sponsored by Global ... physical activity. The fun run is geared towards children of all ages; it ...
(Date:10/13/2017)... ... October 13, 2017 , ... Talented host, actor Rob Lowe, ... in a new episode of "Success Files," which is an award-winning educational program ... investigates each subject in-depth with passion and integrity. , Sciatica occurs when the ...
Breaking Medicine News(10 mins):
(Date:10/11/2017)... , Oct. 11, 2017  Caris Life Sciences ... on fulfilling the promise of precision medicine, today announced ... joined Caris, Precision Oncology Alliance™ (POA) as its 17 ... centers, the St. Jude Crosson Cancer Institute will help ... the use of tumor profiling, making cancer treatment more ...
(Date:10/11/2017)...  Hill-Rom Holdings, Inc. ("Hill-Rom") (NYSE: HRC), today provided ... Piedras, Puerto Rico , where the ... Following a comprehensive onsite ... structural damage, temporary loss of power and minimal water ... manufacturing operations have resumed, and the company expects to ...
(Date:10/10/2017)... , Oct. 10, 2017   West Pharmaceutical Services, ... solutions for injectable drug administration, today shared the results ... Adapter for improving the intradermal administration of polio vaccines. ... Vaccination Summit in May 2017 by Dr. Ondrej ... Department, World Health Organization (WHO), and recently published in ...
Breaking Medicine Technology: