AUSTRIA – One in eight women could be diagnosed with breast cancer during their life. Among the main causes are taking artificial hormones and other environmental influences. Breast cancer can be inherited but also can be caused by a mutation in the gene BRCA1 (BReast CAncer).

The US actress Angelina Jolie is the most famous women with a BRCA1 mutation. She had become known publicly in 2013 for the removal of her breasts. In fact, women with a mutation of the BRCA1 gene have a dramatically high lifetime risk of breast cancer by up to 80 percent. In addition, this has occurred often in recent years and it is a very aggressive form of cancer. The average age of those affected is 40 years.

Uncontrolled proliferation

In 2010, a group of researchers led by Josef Penninger, the Scientific Director of IMBA, discovered that sex hormones can trigger breast cancer via two proteins of bone metabolism called RANK and RANKL. RANK/RANKL translates the information of the sex hormones and sends a signal that stimulates them to grow the breast cells. This happens in every woman during pregnancy and during the menstrual cycle. Spikes over the signal can lead to uncontrolled proliferation of breast cells.

The scientist from Penninger’s research group now made the discovery that RANKL is the decisive factor for the breaking of cancer among genetically related breast cancer by a mutant BRCA1 gene. Their study compared mice carrying a mutation in the BRCA1 gene where RANK / RANKL were active. In the chest there was development of carcinomas and higher grade malignancy (the precursors of carcinoma developed). But when RANK was genetically blocked, no cancers could be detected in any single mouse and in general there was much less malignant changes.

To verify the transferability of their results to humans, scientists isolated, together with researchers of the MED University of Vienna and from Toronto, breast tissue cells from women who had undergone a preventive mastectomy because of BRCA1 mutation. After RANK was blocked, in human cell culture, growth and spread of breast tissue cells were greatly diminished. This observation confirmed the enormous potential of an Anti-RANKL treatment for cancer prevention in humans. In addition, the researchers showed that genetic variants of RANK can be accompanied by higher breast cancer risk – tested in more than 15,000 women with BRCA1 mutations.

Drug with few side effects

First authour Verona Sigl said that their results, published in the journal Cell Research, is exciting because there is already a drug against RANKL on the market known as Denosumab which is an antibody with very few side effects. It binds tightly to RANKL and thereby inhibits its actionability. Currently, Denosumab is prescribed for osteoporosis and bone metastases but Sigl believes after the discovery from this study it could be used for breast cancer prevention in BRCA1 mutation carriers.

Clinical trials are the next step to confirm the efficacy in humans. Then every woman who is tested positive on a BRCA1 mutation could take Denosumab for prevention, to reduce, dramatically, increased breast cancer risk. From this point of view, serious intervention such as a double mastectomy in the case of Angelina Jolie would be prevented.