Featured Research

from universities, journals, and other organizations

The Telomere Crisis: A Crucial Stage In Breast Cancer

Date:
August 11, 2004
Source:
Lawrence Berkeley National Laboratory
Summary:
Telomere crisis is an important early event in the development of breast cancer, and its occurrence can be identified with precision, according to recent findings by a team of scientists at the Department of Energy's Lawrence Berkeley National Laboratory and the University of California at San Francisco.

These confocal microscope images highlight regions of chromosomes in cells of a breast duct exhibiting hyperplasia (left) and one exhibiting carcinoma in situ (right).
Credit: Image courtesy of Lawrence Berkeley National Laboratory

BERKELEY, CA – Telomere crisis is an important early event in the development of breast cancer, and its occurrence can be identified with precision, according to recent findings by a team of scientists at the Department of Energy's Lawrence Berkeley National Laboratory and the University of California at San Francisco. Their report is now available through advance online publication of Nature Genetics.

Joe Gray, director of Berkeley Lab's Life Sciences Division and a professor of laboratory medicine and radiation oncology at UCSF, is one of the paper's lead authors, with Koei Chin and Britt Marie Ljung of UCSF; Carlos Ortiz de Solorzano, Paul Yaswen, and Martha Stampfer of Berkeley Lab; and Stephen J. Lockett from the National Cancer Institute.

In the breast, cells in a milk-collecting duct occasionally proliferate excessively due to development of a regulatory defect. Gray and his colleagues postulate that this results in a lesion called "usual ductal hyperplasia."

"The chromosomes in these growing cells lose a hundred or so base pairs of DNA every time they divide," Gray explains, "because the usual DNA replication processes don't copy DNA all the way out to the ends of the chromosomes. This erodes the DNA sequences that interact with proteins to form structures called telomeres, which protect the chromosome ends."

Eventually the DNA ends erode so much they can no longer protect the chromosomes. When this happens the chromosomes become unstable, and damage-control mechanisms kick in that kill the unstable cells. This process, known as "telomere crisis," normally protects against inappropriate long-term cell growths like cancer.

Gray and his colleagues believe that "very rarely, the chromosome instability activates a specialized DNA-replication complex, telomerase, which can restore telomeres. Cells in which telomerase is activated can then proliferate indefinitely to form the next stage of cancer, known as 'ductal carcinoma in situ.'" Should the cancer progress further, it next invades other parts of the breast and may escape to other organs.

Not all cancer researchers agree that telomere crisis in hyperplasia, followed by reactivation of telomerase, leads to carcinoma in situ — and thence, sometimes, to invasive cancer; they assign cancer to other causes. Partly the disagreement arises because sequential events can't be followed in individual tissue samples from living subjects.

"In human studies, the order from normal ducts, to ductal hyperplasia, to ductal carcinoma in situ, to invasive cancer is just association," says Gray, "because we can't look at the same tissue all the way through the crisis."

Therefore the researchers compared the assumed sequence of events in tissue with what happened when they induced a culture of human mammary epithelial cells, HMEC, derived from normal breast tissue, to undergo telomere crisis and immortalization. Says Gray, "With HMEC in vitro we can follow the progression all the way through crisis, compare this to what we observe in actual tissue specimens from patients, and see if they are similar."

Using 3-D confocal microscopy and working first with breast-cancer tissue samples, at each stage the researchers assessed genomic instability and such correlated features as the amount of DNA content, signs of rearranged chromosomes, and the number of copies of genes known to play a role in cancer. These measures increased, on average, from the hyperplasia stage to the invasive cancer stage.

They also measured mean telomere lengths of cells at each stage. They found that mean telomere length decreased from normal tissue to carcinoma in situ, and decreased even more in invasive cancers.

When they looked at cultured human mammary cells, the researchers found a remarkably similar series. To induce telomeric crisis and subsequent immortalization in these cells, they introduced a known breast cancer gene into the culture and examined progressive generations of cells.

Telomere length decreased steadily. Genome instability and evidence of rearranged chromosomes were low before telomere crisis — just as in the tissue samples of usual ductal hyperplasia — and highest during the crisis, as in the samples of ductal carcinoma in situ. Instability then decreased, and changes in genome complexity leveled off, as in invasive cancer tissues — where critically short telomeres are presumably maintained by reactivated telomerase.

The mammary cell culture studies also confirmed that the probability of successful passage through the telomere crisis is low — most cells damaged because of shortened telomeres can't evade cell death. In fact, women with usual ductal hyperplasia are only slightly more at risk of developing invasive cancer. When carcinoma in situ does form, it is probably from a single cell that has managed to reactivate telomerase.

"Our research establishes two things," Gray says. "First is that telomere crisis does appear to play an important role in the development of most breast cancers. Second is where it occurs: at the transition from hyperplasia to carcinoma in situ."

These findings suggest that people at higher risk of developing cancer can be identified in advance by measuring telomerase activity, genome instability, and other signals in the clinic.

The findings also point to possible ways of stopping cancer by derailing transition through the telomere crisis (rare as successful transition is): by using drugs that maintain the cell's damage-control mechanisms, for example, or that prevent telomerase reactivation or that poison cells in which telomerase is already active. Some of these possible preventive agents are already being tested.

Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our website at http://www.lbl.gov.


Story Source:

The above story is based on materials provided by Lawrence Berkeley National Laboratory. Note: Materials may be edited for content and length.


Cite This Page:

Lawrence Berkeley National Laboratory. "The Telomere Crisis: A Crucial Stage In Breast Cancer." ScienceDaily. ScienceDaily, 11 August 2004. <www.sciencedaily.com/releases/2004/08/040811081620.htm>.
Lawrence Berkeley National Laboratory. (2004, August 11). The Telomere Crisis: A Crucial Stage In Breast Cancer. ScienceDaily. Retrieved April 18, 2014 from www.sciencedaily.com/releases/2004/08/040811081620.htm
Lawrence Berkeley National Laboratory. "The Telomere Crisis: A Crucial Stage In Breast Cancer." ScienceDaily. www.sciencedaily.com/releases/2004/08/040811081620.htm (accessed April 18, 2014).

Share This



More Health & Medicine News

Friday, April 18, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Obama: 8 Million Healthcare Signups

Obama: 8 Million Healthcare Signups

AP (Apr. 17, 2014) President Barack Obama gave a briefing Thursday announcing 8 million people have signed up under the Affordable Care Act. He blasted continued Republican efforts to repeal the law. (April 17) Video provided by AP
Powered by NewsLook.com
Is Apathy A Sign Of A Shrinking Brain?

Is Apathy A Sign Of A Shrinking Brain?

Newsy (Apr. 17, 2014) A recent study links apathetic feelings to a smaller brain. Researchers say the results indicate a need for apathy screening for at-risk seniors. Video provided by Newsy
Powered by NewsLook.com
Could Even Casual Marijuana Use Alter Your Brain?

Could Even Casual Marijuana Use Alter Your Brain?

Newsy (Apr. 16, 2014) A new study conducted by researchers at Northwestern and Harvard suggests even casual marijuana use can alter your brain. Video provided by Newsy
Powered by NewsLook.com
Thousands Of Vials Of SARS Virus Go Missing

Thousands Of Vials Of SARS Virus Go Missing

Newsy (Apr. 16, 2014) A research institute in Paris somehow misplaced more than 2,000 vials of the deadly SARS virus. Video provided by Newsy
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:
from the past week

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