Preventive Approach for Genetic Breast Cancer Shows Promise

Risk of developing breast cancer in women with a BRCA1 mutation may be reduced.

Researchers found a new preventative method to reduce the risk of developing breast cancer in women with a BRCA1 mutation, who on average have up to an 87% lifetime risk of developing the disease.

Formerly, prophylactic surgery was the only procedure able to significantly reduce the risk of breast cancer, but can result in postoperative complications.

In a previous study conducted in 2010, researchers discovered that sex hormones can trigger breast cancer through the protein RANKL and its receptor RANK, which are key factors in bone metabolism. Additionally, the proteins linked breast cells and sex hormones by giving signals that directed the growth of these breast cells.

This process normally occurs during a woman’s menstrual cycle or pregnancy, but if deregulated, the mammary cells begin to divide and multiply, resulting in breast cancer. The current multinational study published in Cell Research found that RANKL is also the main driver of the breast cancer-driven BRCA1 mutation.

Using BRCA1 mutant mice, researchers showed that by blocking the RANKL/RANK system resulted in largely normal mammary glands, while invasive carcinomas were found in the control group. Next, researchers in Vienna and Toronto used human cultures of isolated breast tissue cells that were retrieved from women with the BRCA1 mutation who had undergone a preventive mastectomy.

The cell cultures showed that RANKL inhibition also resulted in a significant growth reduction and reduced spread of breast cancer cells.

Through collaboration with colleagues in Barcelona and from the CIMBA consortium that mapped more than 23,000 women, researchers showed that the genetic variants in the RANK gene were associated with an increased risk of developing breast cancer in women who carry the BRCA1/2 mutations.

“Our finding is so exciting because there is already an approved drug against RANKL called Denosumab,” said researcher Verena Sigl. “It is an antibody with very few side effects, which binds tightly to RANKL, thereby inhibiting its ability to act. Based on our discovery, the already approved drug Denosumab or other future drugs that will block RANKL/RANK, could be used for breast cancer prevention in BRCA mutation carriers.”

Researchers from the University of Maryland School of Medicine have already tried using a RANKL-blocking drug for preventive use in mice. The mice with BRCA1 mutations were divided into 2 groups.

The control group developed multiple early breast cancer lesions, while the second group that was administered the RANKL blockade had virtually no malignant changes in breast tissue, even after being observed over a longer period of time.

Although phase 3 clinical trials are needed to confirm the efficacy in humans, women who have a BRCA1 mutation could take the RANKL blockade treatment as preventive measure to reduce the significant increased risk of breast cancer.

“This work is a great example of an international collaboration of many scientists with one grand vision: Prevention of breast cancer,” said lead researcher Josef Penninger. “Cancer prevention is one of the key issues we face in medicine today, a world where much fewer women will get breast cancer in the first place. We have also shown that RANKL/RANK are critically involved in sex hormone-driven breast cancer. If the uncovered mechanism indeed works in the prevention of breast cancer in high risk patients, this could possibly be used to prevent breast cancer in general. One door for breast cancer prevention has now been opened and this can be tested very fast.”