Researchers at the Walter and Eliza Hall Institute of Medical Research in Australia have recently shown that an existing medication for osteoporosis may help prevent breast cancer in high-risk patients carrying mutations in the BRCA1 gene. The study, “RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers,” was published in Nature Medicine.
BRCA1 is a protein involved in a number of cellular processes, including maintenance of chromosome integrity and regulation of gene expression, whose faulty expression often leads to breast cancer development. Women who carry mutations in the BRCA1 gene have a 65 percent risk of developing breast cancer by age 70. Nonetheless, the precise mechanism of BRCA1 mutations that leads to breast cancer is not fully understood.
Now, the Australian researchers have revealed that the cancer precursor cells in BRCA1-mutant breast tissue expressed high levels of the receptor RANK. “These cells proliferated rapidly, and were susceptible to damage to their DNA — both factors that help them transition toward cancer,” Emma Nolan, a PhD student at the Walter and Eliza Hall Institute, said in a press release. “We were excited to discover that these precancerous cells could be identified by a marker protein called RANK.”
Identifying RANK as a marker of cancer precursors was a major breakthrough, because inhibitors of the RANK signaling pathway were already approved for clinical use.
“An inhibitor called denosumab is already used in the clinic to treat osteoporosis and breast cancer that has spread to the bone,” said Prof. Geoffrey J. Lindeman, a medical oncologist at The Royal Melbourne Hospital, and the study’s senior author. “We therefore investigated what effect RANK inhibition had on the cancer precursor cells in BRCA1-mutant breast tissue.”
The researchers established 3D cultures of pre-tumor breast tissue isolated from BRCA1-mutant women, and showed that when these samples were treated with denosumab, an inhibitor of the RANK Ligand, the cell proliferation was markedly decreased. Furthermore, denosumab significantly reduced tumor formation and progression in BRCA1-deficient mice.
“This is potentially a very important discovery for women who carry a faulty BRCA1 gene, who have few other options. Current cancer prevention strategies for these women include surgical removal of the breasts and/or ovaries, which can have a serious impact on people’s lives,” Lindeman said. To move the work forward, denosumab would need to be formally tested in clinical trials in this setting because it has not been approved for breast cancer prevention,” he said.
“By thoroughly dissecting how normal breast tissue develops, we have been able to pinpoint the precise cells that are the culprits in cancer formation,” said Prof. Jane Visvader. “It is very exciting to think that we may be on the path to the ‘holy grail’ of cancer research, devising a way to prevent this type of breast cancer in women at high genetic risk.”