Featured Research

from universities, journals, and other organizations

Vanderbilt Cancer Center Discovery May Help Overcome Resistance To Anti-Breast Cancer Drug

Date:
January 7, 1999
Source:
Vanderbilt University Medical Center
Summary:
Vanderbilt Cancer Center researchers have reported a discovery that could help overcome a major obstacle in treating breast cancer with tamoxifen -- the resistance that breast tumor cells commonly develop to this "anti-estrogen" drug.

NASHVILLE, Tenn. -- Vanderbilt Cancer Center researchers have reported a discovery that could help overcome a major obstacle in treating breast cancer with tamoxifen -- the resistance that breast tumor cells commonly develop to this "anti-estrogen" drug.

Related Articles


Writing in the Jan. 6 issue of the Journal of the National Cancer Institute, the researchers report that overproduction of a certain growth factor, called TGF-beta, contributes to tamoxifen resistance. They also demonstrate that the immune system's "natural killer" activity is important for tamoxifen's anti-cancer effects.

Ultimately, both findings might be exploited to keep tumors dormant for longer periods using tamoxifen.

"At some point in the natural history of breast cancer, tumors become resistant to the anti-estrogen tamoxifen," said principal investigator Dr. Carlos L. Arteaga, professor of Medicine and associate professor of Cell Biology.

"The practical implication of this research is that, if we can sort out the mediators of this effect, perhaps we can design strategies to interfere with those mechanisms and markedly prolong the period of tamoxifen response or even reverse tamoxifen resistance."

Tamoxifen, a relatively well-tolerated therapy, has been a part of the arsenal against advanced breast cancer for more than two decades. More recently, it has been used as an additional therapy following surgery or other primary treatment for early stage breast cancer. Tamoxifen is also being studied as a "chemopreventive" to delay the onset of breast cancer in women at high risk of developing the disease.

The drug is called an anti-estrogen because it blocks the effects of the female hormone estrogen. Some breast cancer cells are sensitive to estrogen, which binds to estrogen receptors in these cells and stimulates them to proliferate and invade.

In patients with metastatic breast cancer, tumors typically become resistant to tamoxifen in about 12-18 months, Arteaga said.

Earlier work has suggested that some tamoxifen-resistant breast cancers produce abnormally high levels of transforming growth factor beta (TGF-beta). So Arteaga and his colleagues decided to test whether interfering with the production of TGF-beta would alter this resistance.

The scientists used two estrogen-sensitive human breast cancer cells lines, one that was sensitive to tamoxifen and produced low levels of TGF-beta and a daughter cell line that was resistant to tamoxifen and overproduced TGF-beta. The cells were used to create tumors in mice, which were then treated with tamoxifen.

Tumors with low TGF-beta levels responded to tamoxifen, while the tumors formed by the cells that overproduced TGF-beta did not. However, when antibodies to block TGF-beta were added to tamoxifen, these resistant tumors became sensitive to the drug. "This suggested to us that TGF-beta was mediating the resistance to the anti-estrogen," Arteaga said.

When the cell lines were studied in culture rather than in the animal, however, adding TGF-beta antibodies did not restore tamoxifen sensitivity. This strongly suggested that something in the mouse -- but absent in the cell cultures -- was involved in the development of tamoxifen resistance.

The researchers suspected that the mechanism was the host's "natural killer" (NK) immune activity for two reasons. First, tamoxifen is known to increase NK activity. Second, TGF-beta is a powerful suppressor of NK function. So if tamoxifen needs to increase NK activity to be effective, and if TGF-beta decreases that activity, it would make sense that increased TGF-beta levels would result in a reduced anti-tumor effect by tamoxifen.

To test their hypothesis, the researchers repeated the experiment in "beige mice," which lack natural killer activity. They found that the combination of tamoxifen and TGF-beta antibodies did not have an anti-tumor effect in the beige mice bearing tamoxifen-resistant tumors. In addition, they discovered that in tamoxifen-sensitive tumors that produced low levels of TGF-beta, the effect of tamoxifen was statistically greater in the mice with NK activity than in those that lacked it.

"There are many potential ways, some in development, to inhibit TGF-beta, so I'm hopeful we can test combinations of these inhibitors with tamoxifen to see if we can enhance the effects of tamoxifen in women whose breast cancers overproduce TGF-beta," Arteaga said.

This research also has implications for patients whose NK activity is suppressed, Arteaga said. "It is not uncommon to see NK activity suppressed in patients with cancer, so we believe that, in some cases, NK function may be down-regulated by something that the tumor produces," he said.

"There are ways to boost NK activity, so perhaps we can use those to increase the response to tamoxifen."

The work was supported by the National Cancer Institute and the Susan G. Komen Breast Cancer Foundation.

More information about the Vanderbilt Cancer Center, which is designated as a leader in cancer care and research by the National Cancer Institute, can be found at the Vanderbilt Cancer Center website at http://www.mc.vanderbilt.edu/vumc/centers/cancer.


Story Source:

The above story is based on materials provided by Vanderbilt University Medical Center. Note: Materials may be edited for content and length.


Cite This Page:

Vanderbilt University Medical Center. "Vanderbilt Cancer Center Discovery May Help Overcome Resistance To Anti-Breast Cancer Drug." ScienceDaily. ScienceDaily, 7 January 1999. <www.sciencedaily.com/releases/1999/01/990107074317.htm>.
Vanderbilt University Medical Center. (1999, January 7). Vanderbilt Cancer Center Discovery May Help Overcome Resistance To Anti-Breast Cancer Drug. ScienceDaily. Retrieved October 26, 2014 from www.sciencedaily.com/releases/1999/01/990107074317.htm
Vanderbilt University Medical Center. "Vanderbilt Cancer Center Discovery May Help Overcome Resistance To Anti-Breast Cancer Drug." ScienceDaily. www.sciencedaily.com/releases/1999/01/990107074317.htm (accessed October 26, 2014).

Share This



More Health & Medicine News

Sunday, October 26, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Texas Nurse Nina Pham Cured of Ebola

Texas Nurse Nina Pham Cured of Ebola

AFP (Oct. 25, 2014) — An American nurse who contracted Ebola while caring for a Liberian patient in Texas has been declared free of the virus and will leave the hospital. Duration: 01:01 Video provided by AFP
Powered by NewsLook.com
Toxin-Packed Stem Cells Used To Kill Cancer

Toxin-Packed Stem Cells Used To Kill Cancer

Newsy (Oct. 25, 2014) — A Harvard University Research Team created genetically engineered stem cells that are able to kill cancer cells, while leaving other cells unharmed. Video provided by Newsy
Powered by NewsLook.com
IKEA Desk Converts From Standing to Sitting With One Button

IKEA Desk Converts From Standing to Sitting With One Button

Buzz60 (Oct. 24, 2014) — IKEA is out with a new convertible desk that can convert from a sitting desk to a standing one with just the push of a button. Jen Markham explains. Video provided by Buzz60
Powered by NewsLook.com
Ebola Protective Suits Being Made in China

Ebola Protective Suits Being Made in China

AFP (Oct. 24, 2014) — A factory in China is busy making Ebola protective suits for healthcare workers and others fighting the spread of the virus. Duration: 00:38 Video provided by AFP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins