A new international study has discovered how a variant of the BRCA1 gene helps breast cancer to grow by knocking out a tumor suppressor gene called PTEN. The researchers believe their discovery could lead to new ways to treat this aggressive type of breast cancer.The study is published in the early online edition of the journal Nature Genetics and is the work of researchers at Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center in the US, and Lund University in Sweden.
Study co-author, Dr. Ramon Parsons, who is director of the Avon Foundation Breast Cancer Research Laboratory and also director of the Breast Cancer Program of the Herbert Irving Comprehensive Cancer Center at Columbia University Medical Center and New York Presbyterian Hospital, said in a prepared statement:
"These findings are exciting because ever since the link was established between BRCA1 and breast cancer more than 10 years ago, we have been frustrated by our lack of understanding about how mutations in this gene cause breast cancer."
"We have been stymied by our limited resources to treat these cancers, which are associated with very poor prognoses. Now that we know that PTEN is involved, we finally have a target for therapy for these cancers," he added.
Parsons led one of the two teams in 1997 that independently revealed that PTEN, a key tumor suppressor gene, was knocked out in breast, brain and prostate cancers.
Scientists now know that PTEN mutations are second only to p53 as being the most frequently present in all cancers, affecting about 30 per cent of them.
Disabling PTEN switches on a strong signal that encourages tumor growth. This is different to the direct effect of the BRCA1 mutation itself, which causes cells to be more vulnerable to genetic damage and indirectly sends out cell growth signals. As Parsons explained:
"Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer."
PTEN mutations increase the activity of various proteins via the PTEN/PI3K pathway to promote tumor growth. Phase I clinical trials investigating the effect of shutting down proteins in this pathway as a way to stop tumor growth are already under way, said the researchers.
Parsons and colleagues used a new technique to find the link between BRCA1 and PTEN; more conventional ways of searching for mutations had failed. The new method looks for physical breaks in chromosomes.
They examined 34 biopsies from women with BRCA1 tumors and found in about one third of them that the PTEN gene was incomplete. In some cases large sections of the gene were missing, and in others one half of the gene had come away and was reattached to other parts of the chromosome.
The researchers said that lack of BRCA1 in tumors can lead to this type of chromosome damage because BRCA1 is involved in PTEN repair. Women with breast cancer who have normal BRCA1 rarely have such large mutations in PTEN, they said.
Parsons and colleagues estimate that PTEN mutations affect about 50 per cent of BRCA1 breast cancers.
BRCA1 causes a type of breast cancer called basal-like or triple negative, because the tumors are missing receptors for estrogen, progesterone, and HER2, which are needed for treatment to work.
The study showed that PTEN is also damaged in most tumors from basal-like cancer, which occurs in 10 to 20 per cent of women with breast cancer not caused by inheriting a faulty BRCA1 gene.
Lead author Dr. Lao Saal, who at the time of the research was a fellow in Parsons' Avon Foundation Breast Cancer Research Laboratory and is now finishing his medical degree at Columbia University College of Physicians and Surgeons, said that:
"Our results point to PTEN as a major player in both hereditary and non-hereditary basal-like breast cancer, a finding that may now be exploited to develop new therapeutic strategies to improve outcomes for women with these aggressive tumors."
Parsons, Saal, and colleagues suggest BRCA1 also affects other cancer genes, and there may be similar links between another breast cancer gene, BRCA2 and mutations in other genes. They hope to use the new chromosome scanning technique to track down other mutated genes involved in the development of breast cancer:
"These kinds of mutations that break tumor suppressors in half may turn out to be common in many kinds of carcinomas, particularly those with deficiencies in DNA repair pathways similar to BRCA1, a question that only a systematic search can answer," explained Saal.
Dr. Åke Borg, professor of oncology at Lund University and study co-author said:
"Similar research is underway in tumors from carriers of germline mutations in BRCA2, the other known major breast cancer susceptibility gene."
"BRCA2 has a role downstream in the same DNA double strand break repair pathway as BRCA1, but tumors from BRCA2 mutation carriers have a quite different phenotype compared to BRCA1 tumors, less often involving PTEN loss. However, like BRCA1, BRCA2 tumors have an instable genome with massive chromosomal aberrations, suggesting that other genes may be targeted," explained Borg.
Basal-like breast cancer tumors are among the most aggressive tumors, they grow fast and spread quickly, are resistant to standard breast cancer treatments such as Tamoxifen or Herceptin, and are more likely to be fatal than other cancers.
Between 60 and 80 per cent of women carrying a BRCA1 mutation will have breast cancer. BRCA1 mutations are more common among African-American women and women of Ashkenazi Jewish descent.
Women who inherit BRCA1 and BRCA2 mutations are also more likely to get ovarian cancer, a disease that is often undetected in the early stages so currently the prognosis is very poor for most women who eventually discover they have it.
See Full Article
No comments:
Post a Comment