Inflammation and the tumour microenvironment in breast cancer: The role of Stat3 and NF-kB

Breast cancer is a common disease in post-menopausal women. Although surgery and chemotherapy prolong life, many breast tumours spread to other organs and this metastatic disease causes the death of the patient. There is evidence from epidemiological studies that, although pregnancy can reduce the lifetime risk of breast cancer, women have a higher risk in the 5-10 years following a pregnancy. We propose that this risk is due to the factors that are present in the breast during the period immediately following lactation (involution), when the milk-producing cells die and secrete a number of inflammatory substances. Our studies on the processes that take place during involution have identified some of these factors. In this project, we propose to delete two signaling molecules that are key regulators of involution and measure the effect this has on tumour formation in models of breast cancer. Once we have identified the most important factors, we will compare levels of these in cell lines derived from breast cancer tissues. We will then specifically block these factors in breast cancer cells and measure how this affects their growth and spread in a novel tissue scaffold that we are developing to provide a 3-D model of the breast. It is hoped that this work will reveal new therapeutic targets or markers of breast cancer.

Breast cancer is a common disease in post-menopausal women. It has been known for some time that an early full-term pregnancy reduces the lifetime risk of hormone-responsive breast cancer. However, a woman has a higher risk following a pregnancy and this risk remains for up to 10 years. We hypothesise that the mammary gland, during post-lactational regression (involution), is promotional for tumour growth and metastasis. This is supported by our data demonstrating that mammary epithelial cells secrete inflammatory mediators and cytokines and thus modulate the cellular environment during involution. In this project we aim to test this hypothesis by using mouse models of breast cancer that are crossed to mice that are conditionally null for either Stat3 or NF-kB, transcription factors that we have shown to be essential for the involution process. We have four specific aims. Firstly, we will characterize the inflammatory response during involution and the role of Stat3 and NF-kB is regulating this response. We will investigate also the expression of involution-related inflammatory signals in a panel of breast cancer cell lines. A major objective is to determine whether the environment encountered by tumour cells (using a PyMT or Neu model of breast cancer) during a period of involution influences the rate and extent of tumour growth and the role of Stat3 and NF-kB in this process. Finally, we will select candidate genes and abrogate their expression using RNAi mediated gene knockdown in a breast cancer cell line followed by either xenotransplantation into mammary fad pads or culture in a novel 3-D scaffold system.