London , Dec 10 (ANI): A new research has revealed that it may be possible to treat a highly aggressive form of breast cancer by controlling the mutations in a BRCA1 gene that kills the tumor suppressor gene PTEN.

The study for the first time has disclosed how mutations in the BRCA1 gene lead to breast cancer. Findings reveal that one of the ways through which BRCA1 mutations cause cancer is by knocking out a powerful tumor suppressor gene known as PTEN.

The study was led by Ramon Parsons, M.D., Ph.D., the Avon Foundation Professor of Medicine and Pathology at Columbia University College of Physicians and Surgeons and Ake Borg, Ph.D., professor of oncology at Lund University .

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, Nature quoted Dr. Parsons, as saying.

PTEN, one of the most important tumor suppressor genes altered in breast cancer, as well as in brain and prostate cancers was discovered in 1997 and Dr. Parsons led one of the two teams that discovered it independently.

It is now well known that PTEN can be mutated in almost 30pct of all cancer that makes it the second most mutated gene in cancer after p53. a strong pro-growth signal on tumor cells is sent out after PTEN is killed.

It is quite different from the BRCA1 mutation, which only affects the cells to add genetic damage and sends an indirect signal for cell growth.

Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer, said Dr. Parsons.

Runaway tumor cell growth is promoted by PTEN mutations by increasing the activity of a series of different proteins in the cell known as the PTEN/PI3K pathway.

If any one of those proteins is shut down it could possibly cease cancer growth. Investigational therapies to shut down proteins in the PTEN pathway are currently in Phase I clinical trials.

The researchers made the connection between BRCA1 and PTEN utilizing techniques to search for physical chromosome breaks within the PTEN gene a technique that had never before been used.

However, in the earlier look out for PTEN mutations in BRCA1 tumors the scientists searched for conventional mutations but failed to turn up any abnormalities.

According to Dr. Parsons about 50 percent of BRCA1 breast cancers will be found to harbor PTEN mutated after a complete analysis of chromosomal mutations is done.

Breast cancer tumors caused by BRCA1 are known as basal-like or triple-negative because these tumors usually lack estrogen, progesterone, and HER2 receptors, which are needed for most breast cancer treatments to be effective.

It was found in 10 to 20 percent of women with non-hereditary breast cancer and it was discovered PTEN is also lost in the majority of these breast tumors as well.

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, said Dr. Saal, who at the time of the research, was a fellow in Dr. Parsons Avon Foundation Breast Cancer Research Laboratory.

It was also predicted that cancer genes other than PTEN are targeted by BRCA1.

By using the same techniques we used to find gross chromosomal rearrangements in PTEN, we hope to start identifying additional mutated genes involved in the development of breast cancer, said Dr. Parsons.

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, said Dr. Saal.

Similar research is underway in tumors from carriers of germline mutations in BRCA2, the other known major breast cancer susceptibility gene, said Dr. Borg.

He added: 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.

Basal-like breast cancer tumors, whether caused by BRCA1 mutations or of the non-hereditary type, are among the most aggressive tumors. They are quite fast in growth and spread quickly, making them more susceptible to be fatal than other types of cancer.

These tumors are more likely to be resistant to standard breast cancer treatments, such as Tamoxifen or Herceptin, making them especially difficult to treat. As a result, many young BRCA1 carriers opt to have their breasts prophylactically removed instead of waiting for cancer to appear.

The BRCA1 mutations caused Breast cancers are likely to affect women much earlier, usually before menopause and at times in their 20s and 30s. Almost 60 to 80 percent of women who carry a BRCA1 mutation will develop breast cancer at some point during their lives.

The carriers of BRCA1 mutation are widespread among African-American women and women of Ashkenazi Jewish descent.

Also inherited BRCA1 (and BRCA2) mutations also make women susceptible to ovarian cancer, a disease that is not usually detected through early diagnosis and which has a fatal outcome in advanced stages.

The new study was published online on the Nature Genetics website and it will appear in the January print issue of this journal. (ANI)