Denosumab Blocks Cancer Cell Growth In BRCA1 Breast Cancer

Women with a mutation in the BRCA1 gene could be spared surgery, as Australian researchers announce a common osteoporosis drug may halt the growth of BRCA1 breast cancer cells.

Individuals carrying a faulty BRCA1 gene are at raised risk of developing aggressive breast cancer. Many women with this gene mutation currently choose surgical removal of their breast tissue and ovaries to reduce their chance of developing breast or ovarian cancer.

Actress Angelina Jolie made news in 2013 when she revealed she was opting for the surgery- preventive, bilateral mastectomy.

By identifying the cells that give rise to breast cancers in women who have inherited a faulty version of the BRCA1 gene, Walter and Eliza Hall Institute researchers have found that the drug denosumab (marketed as Prolia) may have potential to prevent breast cancer from developing. If confirmed in clinical trials, this would provide a non-surgical option to prevent breast cancer in women with elevated genetic risk.

The protein produced by the BRCA1 gene normally plays a key role in repairing day-to-day DNA damage. BRCA1 is even regarded a tumor-suppressor gene due to it’s ability to regulate the repair of damaged DNA. When BRCA1 is mutated, however, it can allow cancer to occur with increased frequency.

The RANK Marker Protein

Employing donated samples of breast tissue from women carrying a faulty BRCA1 gene, Ms Emma Nolan, Professor Jane Visvader and Professor Geoff Lindeman were able to pinpoint the cells that give rise to breast cancer. The research, which also involved researchers at the Australian familial cancer consortium kConFab and US biotechnology company Amgen was published in Nature Medicine.

Cancer precursor cells in BRCA1-mutant breast tissue had many similarities to aggressive forms of breast cancer, said Ms Nolan, who is a PhD student at the institute enrolled through The University of Melbourne’s Department of Medical Biology.

“These cells proliferated rapidly, and were susceptible to damage to their DNA – both factors that help them transition towards cancer,” she said. “We were excited to discover that these pre-cancerous cells could be identified by a marker protein called RANK.”

Professor Lindeman, who is also a medical oncologist at The Royal Melbourne Hospital, said the discovery of RANK as a marker of cancer precursors was an important breakthrough, because inhibitors of the RANK signalling pathway were already in clinical use.

“An inhibitor called denosumab is already used in the clinic to treat osteoporosis and breast cancer that has spread to the bone,” he said. “We therefore investigated what effect RANK inhibition had on the cancer precursor cells in BRCA1-mutant breast tissue.”

The research team showed that RANK inhibition switched off cell growth in breast tissue from women with a faulty BRCA1 gene and curtailed breast cancer development in laboratory models.

“We think this strategy could delay or prevent breast cancer in women with an inherited BRCA1 gene mutation,” Professor Lindeman said. “A clinical trial has already begun to investigate this further.

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 serious impacts on people’s lives. To progress this work, denosumab would need to be formally tested in clinical trials in this setting as it is not approved for breast cancer prevention,” Professor Lindeman said.

Professor Visvader said the discovery had its basis in more than a decade of investigations of breast stem cell function.

The work was funded by The National Breast Cancer Foundation, The Qualtrough Cancer Research Fund, The Joan Marshall Breast Cancer Research Fund, the Australian Cancer Research Foundation, Cancer Council Victoria, the Cancer Therapeutics Cooperative Research Centre, an Amgen Preclinical Research Program Grant, the National Health and Medical Research Council, the Victorian Cancer Agency, and the Victorian Government Operational Infrastructure Support Scheme.

Emma Nolan, et al
RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers
Nature Medicine (2016) doi:10.1038/nm.4118

Image: Keoni Cabral/Flickr