The Role of Chemokine Receptors CCR6 and CCR7 in the Initiation and Progression of Breast Cancer

Abstract

Breast cancer is one of the most common causes of cancer-related death in women world-wide. Despite many advances in medical research, incidence and mortality rates still remain high. In the last decade, evidence has emerged that links components of the immune system, including various signalling mediators and cell subsets, with regulation and promotion of breast cancer. Among others, the chemokine superfamily has been heavily implicated in the pathobiology of breast cancer due to their ability to induce cellular migration, proliferation and recruitment of supporting cells to the tumour microenvironment upon binding of cognate chemokine receptors. However, the underlying mechanisms and specific details governing the function of chemokines and their receptors in regulating breast cancer development and progression are largely unknown. This study systematically examined the roles of two chemokine receptors, CCR7 and CCR6, in breast cancer initiation and progression. These receptors had previously been shown to induce cellular proliferation and migration of breast cancer cell lines upon stimulation with chemokine ligands and had been implicated in regulation of other malignancies, but in vivo evidence for their roles had not been shown to date. Using the MMTV-PyMT transgenic mouse model for breast cancer, it was found that deletion of CCR7 significantly delayed mammary tumour onset and reduced both the number of primary tumours and extent of distal metastasis to the lungs. It was further found that CCR7 exerted its tumour-promoting function by maintaining populations of stem-like cancer cells. Stimulation of CCR7 in stem cell-enriched cultures induced self-renewal and the loss of this receptor resulted in a significant decrease in tumour-propagating ability of the cells. Furthermore, pharmacological blockade of CCR7 reduced proportions and activity of stem cell-like pools, indicating that this receptor can potentially be targeted therapeutically to eliminate quiescent cancer stem cells. Deletion of CCR6 in the MMTV-PyMT model also significantly delayed tumour onset, reduced the extent of epithelial hyperplasia, and resulted in a decreased incidence of mammary tumours. However, no evidence was found of a role for CCR6 in mammary epithelium, or in maintenance of the cell lineage hierarchy. Upon further investigation, it was discovered that CCR6 was involved in the recruitment of tumour-promoting macrophages to the mammary tumour microenvironment. CCR6 was highly expressed on tumour-associated macrophages, and the loss of CCR6 significantly reduced the numbers of macrophages present in PyMT-driven mammary tumours. Taken together, cumulative data generated throughout the course of this project conclusively demonstrate that CCR7 and CCR6 both have important roles in the development and progression of breast cancer and may therefore have therapeutic utility in targeting both the transformed mammary epithelium and the supporting tumour microenvironment.Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 201

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