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

孕后乳腺炎症微环境及其在肿瘤发生中的作用

• 批准号: MR/N022963/1
• 负责人: Christine Watson
• 金额: $ 52.06万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN022963%2F1
• 关键词: inflammatory; microenvironment; post; pregnancy; mammary

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.

乳腺（MG）的基本作用是产生乳汁喂养幼崽，因此在哺乳期间，腺体充满了产乳的乳腺细胞。在断奶时，当不再需要牛奶时，这些产奶细胞死亡并被脂肪细胞取代。这个过程被称为退化，被认为是妊娠相关乳腺癌的重要发展。此外，退化导致癌症发展的可能性被认为会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组建家庭，我们很可能会看到越来越多的妊娠相关乳腺癌病例。这项研究计划概述了一些目的和目标，这些目的和目标将帮助我们准确地确定MG的退化如何导致乳腺癌。为了理解这一点，我们使用小鼠模型，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在做什么。我们通过分析细胞在其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，称为巨噬细胞的免疫细胞在MG中积累，以帮助清除大量碎片。这些细胞有助于创造一种独特类型的炎症环境，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。这对于防止不必要的免疫反应造成腺体组织损伤很重要。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妊娠相关乳腺癌的，我们将使用老年小鼠，相当于人类35-40岁的年龄。

项目成果

Tumour cell invasiveness and response to chemotherapeutics in adipocyte invested 3D engineered anisotropic collagen scaffolds.

脂肪细胞投资的 3D 工程各向异性胶原支架中肿瘤细胞的侵袭性和对化疗的反应。

• DOI: 10.17863/cam.30177
• 发表时间: 2018
• 作者: Hume R

The immune environment of the mammary gland fluctuates during post-lactational regression and correlates with tumour growth rate.

• DOI: 10.1242/dev.200162
• 发表时间: 2022-04-15
• 期刊: Development (Cambridge, England)

In conversation with Christine Watson.

与克里斯汀·沃森的对话。

• DOI: 10.1111/febs.16071
• 发表时间: 2022
• 期刊: The FEBS journal
• 作者: Dhillon P

Neutral lineage tracing of proliferative embryonic and adult mammary stem/progenitor cells.

• DOI: 10.1242/dev.164079
• 发表时间: 2018-07-25
• 期刊: Development (Cambridge, England)
• 作者: Lloyd-Lewis B;Davis FM;Harris OB;Hitchcock JR;Watson CJ
• 通讯作者: Watson CJ

The Multifaceted Role of STAT3 in Mammary Gland Involution and Breast Cancer.

• DOI: 10.3390/ijms19061695
• 发表时间: 2018-06-07
• 期刊: International journal of molecular sciences
• 影响因子: 5.6
• 作者: Hughes K;Watson CJ
• 通讯作者: Watson CJ