Breast cancer remains the most frequently diagnosed malignancy in women in the United States, with nearly 317,000 new cases expected in 2025. In addition, experts expect breast cancer to be the second-leading cause of cancer-related mortality in women, resulting in over 42,000 deaths.
According to the American Cancer Society (ACS), risk factors for women developing breast cancer include genetic inheritance of mutations in genes such as BRCA1 or BRCA2, a family history of breast cancer, and having dense breast tissue. However, aging remains the most significant breast cancer risk factor, and 62 is the average breast cancer diagnosis.
Despite knowing that age significantly influences breast cancer risk, scientists lack a complete understanding of how age-related cellular and molecular changes impact breast cancer development. To address this lack of scientific knowledge, a team of researchers initiated a comprehensive study that delved into how aging affects genetic alterations that lead to breast cancer. The researchers recently published the results of their study, which focused on the distinct cell types (epithelial cells, stromal cells, and immune cells) in Nature Aging.
Using mouse models to interrogate aging-related changes in the mammary glands, the researchers found that epithelial cells, the cells that line surfaces, both internal and external, of the body, such as the skin and digestive tract. Epithelial cells in breast tissue line the milk ducts and lobules. We have two types of breast epithelial cells, luminal epithelial cells, the cells that form the inside layer of the breast and produce milk in lactating women, and myoepithelial cells, the cells that form the outside layer of the breast and give structural support to the rest of the tissue in the breast.
The researchers found that aged epithelial cells had genetic alterations in genes that regulate very specific cellular functions. Particularly, the researchers observed changes in metabolic and inflammatory genes that correlated with aging. Metabolism and inflammation both play an important role in cancer development, so alterations in genes related to these mechanisms fit the trend of increasing breast cancer risk.
In addition, the study identified alterations occurring in stromal cells, the cells that make up connective tissue, within the breast. The researchers found that aged stromal cells contained fewer markers associated with fibroblasts, the cells within connective tissue that secrete collagen, while also containing increased markers of fibroblast senescence, a biological process of cellular degradation. These findings suggest aged mammary tissue lacks fibroblasts, possibly due to age-related degradation.
The study also examined changes in immune cell subsets that occurred in aged mammary tissue. The researchers found increased numbers of M2 macrophages, immune cells that can suppress anti-tumor immunity.
The researchers also connected their pre-clinical findings to human malignancy by identifying transcriptional signatures in aging mammary cells in patient breast tumors. This translational aspect of the study not only validates the pre-clinical findings but also suggests more possible links between aging and cancer, providing a potential direction for future research.
The authors conclude that the shifts in the proportions of epithelial, stromal, and immune cells occurring in aged mammary cells can influence breast cancer risk. The study suggests that aging promotes the rewiring of genetic processes within the mammary glands that may lead to breast cancer development. These findings could have significant implications for the diagnosis and treatment of breast cancer, highlighting the practical relevance of the research.
Sources: CA, Nature, Surg Oncol, Nature Aging, Cell Metab, Nature, Eur J Pharmacol