Biological Mechanisms and Therapeutic Opportunities in Mammographic Density and Breast Cancer Risk

SIMPLE SUMMARY: Primary prevention approaches are urgently needed to curb the growing global breast cancer burden. Mammographic density, also known as breast density, is one of the most significant and common independent risk factors for breast cancer. As such, it is an exciting new potential target to reduce the incidence of breast cancer; we could in the future identify women with high mammographic density at an increased risk of breast cancer and take steps to reduce that risk. However, more research is needed to understand the biological mechanisms that underlie high mammographic density and how these might be used to develop new prevention strategies. Here, we review the current knowledge around the biology of mammographic density with a particular focus on immune system factors that could provide new therapeutic targets. ABSTRACT: Mammographic density is an important risk factor for breast cancer; women with extremely dense breasts have a four to six fold increased risk of breast cancer compared to women with mostly fatty breasts, when matched with age and body mass index. High mammographic density is characterised by high proportions of stroma, containing fibroblasts, collagen and immune cells that suggest a pro-tumour inflammatory microenvironment. However, the biological mechanisms that drive increased mammographic density and the associated increased risk of breast cancer are not yet understood. Inflammatory factors such as monocyte chemotactic protein 1, peroxidase enzymes, transforming growth factor beta, and tumour necrosis factor alpha have been implicated in breast development as well as breast cancer risk, and also influence functions of stromal fibroblasts. Here, the current knowledge and understanding of the underlying biological mechanisms that lead to high mammographic density and the associated increased risk of breast cancer are reviewed, with particular consideration to potential immune factors that may contribute to this process.