Elucidating age and pregnancy related alterations in the murine mammary gland
Breast cancer is a heterogeneous disease that is the prevailing cause of cancer-related deaths in women. However, many studies have shown that a full-term pregnancy early in life can decrease the chance of developing cancer by up to 50% during menopause [1]. This is one of the highest protective effects known for any cancer type, and understand- ing the fundamental changes that happen in the mammary gland during pregnancy could be greatly beneficial for tackling this disease with large social implications. In this thesis, we used the mouse model system to investigate the extent and nature of the changes inputted into the mammary gland through ageing and pregnancy and characterised the larger implications of the change in the context of protection against breast cancer using single-cell sequencing as the primary tool. In this investigation we focused on the epithelial cell compartment and found that age and parity affect the luminal progenitor cells most profoundly, with both of them leading to the expansion of alveolar-like cells. Ageing leads to alveolar maturation without prior parity stimulation, and although these cells are similar to cells acquired during parity, they do show some distinguishing qualities. On the other hand, the differences introduced into the mammary gland through parity at a different age are subtle, and in most cases can only be observed when we look at gene set enrichment analysis rather than the effect on individual genes. We found a specific subset of alveolar cells that are retained after all parity-related signals have ceased. Although we did not find conclusive evidence of different levels of retention of these cells post parity at different ages, gene expression in these suggests a higher activity of the P53 pathway, DNA damage response and lower activity of MYC in the young cohort. This suggests that parity at a younger age could have an effect of establishing an environment where the cells are less likely to accumulate tumorigenic insults. Through this work, we created a scRNA sequencing catalogue that can be used for investigating the effects of ageing on the mammary gland composition and gene expression as well as the effect of parity on differently aged animals, both in the context of normal development as well as in the context of disease
pregnancy, brest, mammary gland, single cell RNA sequencing, breast cancer
Networked Digital Library of Theses and Dissertations