Determining the role of macrophages and ageing in involution-associated mammary tumourigenesis

Breast cancer already affects 1 in 8 women in the UK and the incidence of breast cancer is on the increase. Following lactation, the breast undergoes a dramatic remodelling process called involution that induces the death of the milk-producing cells. These dead cells are then removed by a specific type of immune cell called a macrophage. We have shown that macrophages are affected by a factor called Stat3 which is activated during the involution process. Our aim in this project is to investigate the role of macrophages in promoting tumour growth during involution. We also wish to understand the effects of age on both involution and involution-associated cancer development. This work will result in increased understanding of the causes of breast cancer spread during involution and how this is influenced by macrophages. In addition, we hope that we will be able to derive a set of marker genes that are associated with changes in the breasts of older women that predispose them to higher risk of breast cancer.

Breast cancer will affect 1 in 8 women and the incidence rate is rising. While an early full-term pregnancy is protective, post-lactational involution is associated with increased risk and this risk is higher for older women. Experimental evidence in rodents demonstrated that involution is pro-tumourigenic. We hypothesise that inflammatory signalling and the macrophage phenotype during involution is tumour-promotional and that age-related changes in the involuting breast, arising in both the epithelium and the stromal cells, are responsible for the higher cancer risk in involuting older women. The purpose of the proposed project is to address four main questions to improve understanding of the effects of age and the function of macrophages in involution. Firstly, we will address whether the alternatively activated macrophage phenotype is important in promoting involution-associated tumourigenesis and determine whether Stat3 signalling in macrophages affects their phenotype and involution-associated tumourigenesis. Then we will determine if involution-associated tumourigenesis is accelerated with age and is related to macrophage function. Finally, we will derive a molecular signature of age-related changes in involuting mammary gland that will provide markers for increased risk. This project will enhance our knowledge of the critical link between inflammation and neoplastic transformation, and will suggest new approaches to prevent involution-associated tumourigenesis.

This work will have impact in a number of areas. Firstly, and most importantly, it will advance knowledge in two areas of medical science: 1) understanding the basic biology of development in a complex biological system; and 2) improving understanding of breast tumourigenesis. This project will develop a novel approach to investigate experimentally, the role of macrophages and ageing in breast cancer. This has not been attempted before and could have a major impact in understanding of the epidemiological phenomenon of increased risk following a late pregnancy. This knowledge will be useful to breast oncologists as it may highlight the mechanism by which the breast ages and how this impact on tumourigenesis and provide possible avenues for the development of new breast cancer therapies.

This project will provide an opportunity to engage the public in mammary gland biology, breast cancer research and basic research methods. The Watson laboratory has taken part in the Cambridge Science Festival for the past 5 years. This project can be incorporated into this exhibit and will have an impact on public understanding of science and breast cancer research. Finally, in addition to publication of research in scientific journals, members of the laboratory regularly give talks and seminars at universities and research institutions throughout the UK and the world and present their work at international conferences. This provides impact on an international level.

The University of Cambridge, as a teaching institution, affords opportunities for fellows to engage in teaching at various levels. In addition to lecturing to undergraduates, supervision of Part II project students is possible. This is mutually beneficial for all concerned as the fellows gain teaching experience and associated skills and the students are able to work with scientists and clinicians doing research at the cutting edge.