Immune cell location and function during post-natal mammary gland development.

Post-natal mammary gland development requires complex interactions between the epithelial cells and various cell types within the stroma. Recent studies have illustrated the importance of immune cells and their mediators during the various stages of mammary gland development. However, the mechanisms by which these immune cells functionally contribute to mammary gland development are only beginning to be understood. This review provides an overview of the localization of immune cells within the mammary gland during the various stages of post-natal mammary gland development. Furthermore, recent studies are summarized that illustrate the mechanisms by which these cells are recruited to the mammary gland and their functional roles in mammary gland development.

Interleukin-1beta and fibroblast growth factor receptor 1 cooperate to induce cyclooxygenase-2 during early mammary tumourigenesis.

INTRODUCTION: Inflammation within the tumour microenvironment correlates with increased invasiveness and poor prognosis in many types of cancer, including breast cancer. We have previously demonstrated that activation of a mouse mammary tumour virus (MMTV)-driven inducible fibroblast growth factor receptor 1 (iFGFR1) transgene in mammary epithelial cells results in an inflammatory response characterised by induction of inflammatory genes in the mammary gland. Specifically, we have observed increased levels of IL-1beta expression in the mammary gland following activation of iFGFR1 and have used the iFGFR1 model to elucidate the function of IL-1beta in promoting iFGFR1-induced mammary lesions. METHODS: To determine the functional consequences of IL-1beta induction during FGFR1-induced mammary tumourigenesis, the effects of IL-1beta inhibition on the formation of epithelial hyperplasias were examined using the MMTV-iFGFR1 transgenic mouse model. Further studies used a combination of the HC-11 mammary epithelial cell line that stably expresses iFGFR1 and the MMTV-iFGFR1 transgenic mice to further define the mechanisms of IL-1beta function. RESULTS: Inhibition of IL-1beta activity in vivo resulted in reduced iFGFR1-induced epithelial proliferation and formation of hyperplastic structures. Further studies demonstrated that treatment of mammary epithelial cells with IL-1beta-induced expression of cyclooxygenase (Cox)-2 both in vitro and in vivo. Finally, inhibition of Cox-2 prior to activation of iFGFR1 in the transgenic mice also resulted in decreased iFGFR1-induced formation of hyperplastic structures. CONCLUSIONS: The results from these studies indicate that targeting the inflammatory cytokine IL-1beta partially inhibits iFGFR1-induced formation of early-stage mammary lesions, in part through induction of Cox-2. These findings demonstrate that activation of a growth factor receptor in mammary epithelial cells results in increased expression of inflammatory mediators, which cooperate to promote the initiation of hyperplastic lesions in the mammary gland.

Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner.

Tumor formation is an extensive process requiring complex interactions that involve both tumor cell-intrinsic pathways and soluble mediators within the microenvironment. Tumor cells exploit the intrinsic functions of many soluble molecules, including chemokines and their receptors, to regulate pro-tumorigenic phenotypes that are required for growth and progression of the primary tumor. Previous studies have shown that activation of inducible FGFR1 (iFGFR1) in mammary epithelial cells resulted in increased proliferation, migration, and invasion in vitro and tumor formation in vivo. These studies also demonstrated that iFGFR1 activation stimulated recruitment of macrophages to the epithelium where macrophages contributed to iFGFR1-mediated epithelial cell proliferation and angiogenesis. The studies presented here further utilize this model to identify the mechanisms that regulate FGFR1-induced macrophage recruitment. Results from this study elucidate a novel role for the inflammatory chemokine CX3CL1 in FGFR1-induced macrophage migration. Specifically, we illustrate that activation of both the inducible FGFR1 construct in mouse mammary epithelial cells and endogenous FGFR in the triple negative breast cancer cell line, HS578T, leads to expression of the chemokine CX3CL1. Furthermore, we demonstrate that FGFR-induced CX3CL1 is sufficient to recruit CX3CR1-expressing macrophages in vitro. Finally, blocking CX3CR1 in vivo leads to decreased iFGFR1-induced macrophage recruitment, which correlates with decreased angiogenesis. While CX3CL1 is a known target of FGF signaling in the wound healing environment, these studies demonstrate that FGFR activation also leads to induction of CX3CL1 in a tumor setting. Furthermore, these results define a novel role for CX3CL1 in promoting macrophage recruitment during mammary tumor formation, suggesting that the CX3CL1/CX3CR1 axis may represent a potential therapeutic approach for targeting breast cancers associated with high levels of tumor-associated macrophages.