Health-Medical-Fitness-Diet-zk: BRCA1

Se afișează postările cu eticheta BRCA1. Afișați toate postările

marți, 13 decembrie 2011

How Do BRCA1 Mutations Harm Breast Cells? Researchers Demonstrate

Editor's Choice
Academic Journal
Main Category: Breast Cancer
Also Included In: Cancer / Oncology; Genetics
Article Date: 13 Dec 2011 - 9:00 PST

email to a friend printer friendly opinions
not yet rated 5 stars
Researchers at the Johns Hopkins Kimmel Cancer Center have demonstrated during their work with breast cells that breast cells become vulnerable to cancer if a single copy of the breast cancer gene BRCA1 is inactivated. It causes genetic instability in the cells through reducing their ability to repair DNA damage.

The leading risk factor for hereditary breast cancer is an inherited mutation in the BRCA1 gene which requires close monitoring or prompt preventive mastectomy.

The breakthroughs might help researchers develop a drug that prevents hereditary breast cancer, as well as tools to identify those who benefit most from prophylactic treatments. The study is published in the Proceedings of the National Academy of Sciences Oct. 25.

Exactly how BRCA1 inactivation increases the risk of cancer has remained a mystery. BRCA1 is believed to be a "tumor suppressor" gene. Usually, cancer is not caused by the loss of one copy of such genes, as each individual is born with two copies of each gene (one from each parent), and the second copy is sufficient in keeping cells healthy in a similar way that a car can stop safely after losing control of the front brakes as the rear brakes are still working.

According to the researchers, cancer seems to develop in such cases only after the second copy of the gene is damaged, i.e. random mutation during cell division, resulting in uncontrolled cell growth.

Mouse models of BRCA-related cancers have demonstrated that damage to genes, such as TP53, occurred prior to damage to the second copy of BRCA.

Ben Ho Park, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center, explained:

"In theory, this process would take a long time and BRCA-related breast cancers
occur at an early age."

For the investigation, the team used novel technology in order to insert a single copy of a typical BRCA1 mutation into normal breast cells.

The main theory has been that the original inactivation of a single copy of BRCA1 produces additional DNA mutations to expand more rapidly than normal - a condition called "genomic instability."

Park explains:

"The protein coded by BRCA1 is involved in repairing major DNA breaks, so it would make sense that its inactivation could weaken a cell's resistance to DNA mutations."

However, Park adds that the consequence of losing a single copy of BRCA1 was hard to model and difficult to investigate. Results from prior attempts to produce mice with single-copy BRCA1 mutations were uncertain as the mice were unable to demonstrate the pattern of human cancers. Furthermore, it has been hard for investigators to create human cell lines in which the only flaw is a single mutated copy of BRCA1.

In order to test their theory, the team first selected cell lines obtained from non-cancerous human breast epithelial cells - where BRCA1 breast cancers originate. An advanced gene-targeting method was then used to generate novel cell lines that have a typical cancer-associated BRCA1 mutation in just one copy of the gene.

? Following this, tests were conducted on both cell types - cells with the BRCA1 mutation, and the original cells with two healthy copies of BRCA1 - to compare their DNA repair activity. The team demonstrated that cells with BRCA1 mutations were not as effective at carrying out the type of DNA repair known to involve the BRCA1 protein.

They found that when exposed to a DNA-damaging chemotherapy medication or radiation the BRCA1-mutated cells were more likely to die. In addition, BRCA1-mutated cells that were allowed to divide for many weeks were more likely to lose additional genes, includes those frequently mutated in breast tumors. Similar genetic losses were observed on non-cancerous breast cells taken from women with BRCA1 mutations.

Park said:

"What this shows is that having only a single working copy of BRCA1 really does bring about changes in a cell that would be expected to give rise to cancer.
We hope to use this new system to introduce other known BRCA1 mutations, to get a better idea of the relative cancer risk each individual mutation represents, because right now there are few good ways to do that. In the future, we hope to further define risk so that family members with one type of BRCA1 mutation may be advised to get preventative treatment or surgery, and those with other BRCA1 mutations could rely on careful screening."

In addition, the cell models might be helpful in determining the susceptibility of various BRCA1 mutations to drugs, Park adds. At present, anti-cancer medications known as PARP inhibitors are in clinical trials against tumors with BRCA1-mutations.

The lifetime risks of developing breast cancer has been shown among women born with a mutated copy of BRCA1 to range between 50% to 90%. In addition, they have high, but variable risks of ovarian and other cancers.

Written by Grace Rattue
Copyright: Medical News Today
Not to be reproduced without permission of Medical News Today

Visit our breast cancer section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report:

MLA

Grace Rattue. "How Do BRCA1 Mutations Harm Breast Cells? Researchers Demonstrate." Medical News Today. MediLexicon, Intl., 13 Dec. 2011. Web.
13 Dec. 2011. APA

Please note: If no author information is provided, the source is cited instead.

Please note that we publish your name, but we do not publish your email address. It is only used to let you know when your message is published. We do not use it for any other purpose. Please see our privacy policy for more information.

If you write about specific medications or operations, please do not name health care professionals by name.

All opinions are moderated before being included (to stop spam)

Contact Our News Editors

For any corrections of factual information, or to contact the editors please use our feedback form.

Please send any medical news or health news press releases to:

Note: Any medical information published on this website is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional. For more information, please read our terms and conditions.

View the original article here

vineri, 9 decembrie 2011

Scientists Show How BRCA1 Cancer Gene Mutations Harm Breast Cells

Main Category: Breast Cancer
Also Included In: Genetics
Article Date: 09 Dec 2011 - 2:00 PST

email to a friend printer friendly opinions
not yet rated
Working with human breast cells, researchers at the Johns Hopkins Kimmel Cancer Center have shown how the inactivation of a single copy of the breast cancer gene BRCA1 leaves breast cells vulnerable to cancer by reducing their ability to repair DNA damage, causing genetic instability. An inherited mutation in BRCA1 is the leading risk factor for hereditary breast cancer, prompting preventive mastectomies or close monitoring. The new findings may aid development of drugs to prevent hereditary breast cancer and tools to identify women who benefit most from prophylactic treatments.

Precisely how BRCA1 inactivation raises cancer risk has remained something of a puzzle. BRCA1 is considered a "tumor suppressor" gene, and typically the loss of one copy of such genes is not enough to cause cancer. That's because humans inherit two copies of each gene (one from each parent), and the second copy works well enough to keep cells healthy just as a car can safely stop after losing the front brakes since the rear brakes are still intact. Cancer apparently develops in such cases only after the second copy is inactivated in a cell, perhaps by some random mutation during cell division, resulting in the "second hit" causing uncontrolled cell growth as if the cell lost its "brakes."

Mouse models of BRCA-related cancers have shown that "hits" to genes such as TP53 occur before the second "hit" to the remaining functional copy of BRCA. "In theory, this process would take a long time, and BRCA-related breast cancers occur at an early age," according to Ben Ho Park, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.

For the study, reported in the Proceedings of the National Academy of Sciences Oct. 25, Park and his team at Johns Hopkins took advantage of new technology to introduce a single copy of a typical BRCA1 mutation into normal breast cells.

The leading hypothesis has been that the original inactivation of a single copy of BRCA1 causes further DNA mutations to accumulate more quickly than normal a condition called "genomic instability." The protein coded by BRCA1 is involved in repairing major DNA breaks, so it would make sense that its inactivation could weaken a cell's resistance to DNA mutations, says Park.

But the consequence of losing a single copy of BRCA1 was not easy to model or study, he adds. Previous efforts to create mice with single-copy BRCA1 mutations had uncertain results because the mice failed to show the pattern of human cancers. Researchers also have found it difficult to create human cell lines in which the only flaw is a single mutated copy of BRCA1.

To test the idea, Park's team first selected cell lines derived from non-cancerous human breast epithelial cells where BRCA1 breast cancers originate. They then used an advanced gene-targeting technique to create new cell lines that have a typical cancer-linked BRCA1 mutation in only one copy of the gene.

Park's team then ran tests on the two cell types the ones that had the BRCA1 mutation, and the original cells that had two healthy copies of BRCA1 and compared their DNA repair activity. They were able to show that cells with BRCA1 mutations were less efficient at conducting the type of DNA repair known to involve the BRCA1 protein. The BRCA1-mutated cells were more likely to die when exposed to a DNA-damaging chemotherapy drug or radiation. BRCA1-mutated cells allowed to divide for several weeks also were more likely to lose other genes, including genes often mutated in breast tumors. Tests on non-cancerous breast cells taken from women with BRCA1 mutations showed similar genetic losses.

"What this shows is that having only a single working copy of BRCA1 really does bring about changes in a cell that would be expected to give rise to cancer," Park says.

Park plans additional experiments on their new cell models of BRCA1-mutations. "We hope to use this new system to introduce other known BRCA1 mutations, to get a better idea of the relative cancer risk each individual mutation represents, because right now there are few good ways to do that," he says. "In the future, we hope to further define risk so that family members with one type of BRCA1 mutation may be advised to get preventive treatment or surgery, and those with other BRCA1 mutations could rely on careful screening."

The new cell models also may be useful in determining the susceptibility of various BRCA1 mutations to drugs, he adds. Anti-cancer drugs known as PARP inhibitors are currently in clinical trials against tumors with BRCA1-mutations.

Women born with a mutated copy of BRCA1 have been shown to have lifetime risks of breast cancer between 50 and 90 percent, a wide range. They also have high, but variable, risks of ovarian and other cancers.

Article adapted by Medical News Today from original press release. Source: Johns Hopkins Medicine
Visit our breast cancer section for the latest news on this subject. Please use one of the following formats to cite this article in your essay, paper or report: