Existing drug may prevent BRCA1-related breast cancer
John Murphy, MDLinx | May 31, 2016
A drug already approved to treat osteoporosis could also be used to prevent breast cancer due to BRCA1 mutation. If validated, this could quickly lead to the first drug for breast cancer prevention, according to a study published online May 31, 2016 in the journal Cell Research.
Inhibiting a protein (and its receptor) led to normal mammary glands in mice carrying the BRCA1 mutation (left), but malignant changes and carcinomas appeared in mutation-carrying control mice (right). (Images: IMBA)
Women with the BRCA1 mutation have an up to 87% lifetime risk of developing breast cancer. Prophylactic mastectomy is currently the only procedure that significantly reduces breast cancer risk, but is also often associated with postoperative complications, the researchers noted.
In previous research, the investigators had already shown that a bone-building protein—RANKL, along with its receptor RANK—controls progestin-driven breast cancer. Because RANK signaling acts on progenitor cells (believed to be “seed cells” for triple-negative breast cancer in carriers with BRCA1/2 mutations), the investigators speculated that RANKL/RANK might be involved in the etiology of breast cancer due to BRCA mutation.
In this multicenter international study, the researchers found that RANKL is indeed the main driver of BRCA1 mutation-driven breast cancer. Taking this finding one step further, they inhibited the RANKL/RANK system in two mouse models. They found that this inhibition markedly delayed the onset, reduced the incidence, and attenuated the progression of BRCA1 mutation-driven breast cancer.
“Our finding is so exciting because there is already an approved drug against RANKL called denosumab. It is an antibody with very few side effects, which binds tightly to RANKL, thereby inhibiting its ability to act,” said researcher Verena Sigl, a PhD student at the Austrian Institute of Molecular Biotechnology (IMBA), in Vienna, Austria.
She added, “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.”
To determine how these results could be relevant for humans, the investigators isolated breast tissue cells from women who had undergone preventive mastectomy due to BRCA mutation. The researchers found that RANKL and RANK were highly expressed in pre-malignant lesions and breast cancer in women carrying the mutation.
These findings highlight the potential value for inhibiting RANKL in BRCA1-associated cancers at the early stages of tumorigenesis, the authors concluded.
“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,” said study co-author Josef Penninger, PhD, MD, Scientific Director of IMBA. “One door for breast cancer prevention has now been opened, and this can be tested very fast.”
To do so, careful phase III clinical trials are now needed to find out whether inhibiting RANKL in humans provides an advantage over current cancer treatments, Dr. Penninger noted.
In addition to breast cancer, BRCA1 mutation carriers are also at high risk of ovarian cancer. So further research will need to explore whether blocking RANKL can also prevent ovarian carcinogenesis, the authors added.