Targeting RANK pathway in mammographic density and breast cancer prevention

Written by Chee Teik Lee, medical student at University College Dublin and participant in the 2019 Institute for Public Health Summer Research ProgramPublic & Global Health Track

Breast cancer is the most common invasive cancer in women. Age, obesity, and mammographic density are strong risk factors for breast cancer. Modifiable lifestyle factors such as alcohol consumption, physical activity, and smoking take a long time to have an impact on risk reduction (time until benefit) for breast cancer. Obese postmenopausal women are at an increased risk for breast cancer.

Amongst the risk factors being assessed by Engmann NJ et al., mammographic density is one of the strongest determinants that have a relative risk > 4 for breast cancer. In a study published by Engmann NJ et al. in JAMA Oncology (2017) – population attributable risk proportion (the incidence risk in the overall population that can be attributed to the exposure) for breast density in premenopausal women is 39.%3 and 26.2% for postmenopausal women. This shows strong positive relationship between mammographic breast density and breast cancer.

RANKL Signaling Axis

Tamoxifen, a selective estrogen receptor modulator (have the possibility to selectively inhibit or stimulate estrogen-like action in various tissues), is the only FDA-approved chemopreventive drug in premenopausal women. It takes the shortest time (around two years) to reduce breast cancer risk. Tamoxifen reduces breast density by 63% if it is being taken daily for 18 months. However, due to its high toxicity profile, less than three percent of women worldwide are using it. Premenopausal women who take tamoxifen could potentially be at increased risk for endometrial cancer as they start showing signs of menopause.

Several Genome Wide Association Studies, (GWAS is an observational study of a genome-wide set of genetic variants in different individuals to see if any variant is associated with a trait) suggest that mammographic density and breast cancer share very similar genetic pathways. Genetic polymorphisms (variants) identified to date are only responsible for three percent of the difference in mammographic density so modifiable lifestyle factors play a huge role. However, biological basis of mammographic density and how dense breasts increase BC risk are still poorly understood. To date, what we know is
– Alcohol consumption has a weak association
– Obesity has an inverse association
– Physical activity has no association
– HRT (hormone replacement therapy) is not being assessed since it is not applicable in premenopausal women
– Adult diet has no supporting evidence so far

On the other hand, RANK pathway – a signaling pathway discovered in 1997, has proved to have an impact on mammographic breast density. It was originally known for its crucial role in osteoclastogenesis (the development of osteoclast, a large multi-nuclear bone cell which absorbs bone tissue during growth and healing.) RANK signaling pathway is the downstream signaling of progesterone, which is a carcinogen because it increases mammographic density. Desonumab is a humanized monoclonal antibody that works as a RANK ligand (RANKL) inhibitor.

In the treatment of osteoporosis, denosumab binds to RANKL, a protein that is essential for the formation, function and survival of osteoclasts, the cells responsible for bone resorption. Denosumab inhibits osteoclast formation, function and survival, thereby decreasing bone resorption and increasing bone mass and strength. RANK ligand only increases mammographic density prominently when progesterone level is high, and this could be intervened in women with naturally high progesterone levels.

Desonumab is now being studied so that it could be used as an agent to effectively reduce breast density. The only side effect is osteonecrosis (the death of bone tissue due to lack of blood flow) of the jaw.