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

乳腺(MG)的基本作用是产生乳汁喂养幼崽，因此在哺乳期，腺体充满了产奶的乳腺细胞。一旦断奶，当不再需要牛奶时，这些产奶细胞就会死亡，取而代之的是脂肪细胞。这一过程被称为退化，被认为在妊娠相关乳腺癌的发展中起着重要作用。此外，退化会导致癌症发展的概率被认为随着年龄的增长而增加。这一点很重要，因为在当今社会，女性往往推迟到晚年才开始生儿育女，我们很可能会看到越来越多的与怀孕相关的乳腺癌病例。这项研究提案概述了一些目的和目标，将帮助我们准确地确定MG退化是如何导致乳腺癌的。为了理解这一点，我们使用了小鼠模型，我们可以在怀孕后的特定时间点观察MG组织内部，我们可以研究那里的细胞以及它们正在做什么。我们通过分析细胞表面表达的不同标记来做到这一点。我们知道，在退化过程中，免疫细胞巨噬细胞在MG中积累，以帮助清除广泛的碎片。这些细胞有助于创造一种不同类型的炎症环境，在那里它们向其他免疫细胞发出信号，以限制进入腺体的细胞数量。这对于防止不想要的免疫反应对腺体组织的损害很重要。然而，我们认为这些信号产生了一个容易发生癌症的环境。为了测试这一点，我们将使用缺乏这些巨噬细胞或它们产生的分子的转基因小鼠，看看肿瘤是否以同样的方式发展。为了了解年龄是如何导致与怀孕相关的乳腺癌的，我们将使用老龄小鼠，这相当于人类年龄的35-40岁。

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.