The inflammatory microenvironment of the post-pregnancy mammary gland and its role in tumourigenesis

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The fundamental role of the mammary gland (MG) is to produce milk to feed young, thus during lactation the gland is packed with milk-producing mammary cells. Upon weaning, when milk is no longer needed, these milk-producing cells die and are replaced by fat cells. This process is called involution and is thought to be important in the development of pregnancy-associated breast cancer. In addition, the probability that involution will lead to the development of cancer is thought to increase with age. This is important because in today's society, where women often delay starting a family until later in life, it is likely that we will see increasing numbers of pregnancy-associated breast cancer cases.This research proposal outlines a number of aims and objectives which will help us identify exactly how involution in the MG leads to breast cancer. To understand this, we use mouse models where we can look inside the MG tissue at specific time-points following pregnancy, and we can study the cells which are there and what they are doing. We do this by analysing different markers which the cells express on their surface. We know that during involution, immune cells called macrophages accumulate in the MG to help clear the extensive debris. These cells help to create an distinct type of inflammatory environment, where they signal to other immune cells to restrict the number of cells coming into the gland. This is important for preventing tissue damage in the gland by an unwanted immune response. However, we think that these signals generate an environment which is prone to developing cancer. To test this, we will use genetically modified mice which lack these macrophage cells or the molecules they produce, to see if tumours develop in the same way. To understand how age contributes to pregnancy-associated breast cancer, we will use aged mice, which are the equivalent of 35-40 years old in human years.