Abstract
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-1β expression in the mammary gland following activation of iFGFR1 and have used the iFGFR1 model to elucidate the function of IL-1β in promoting iFGFR1-induced mammary lesions.Methods: To determine the functional consequences of IL-1β induction during FGFR1-induced mammary tumourigenesis, the effects of IL-1β 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-1β function.Results: Inhibition of IL-1β 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-1β-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-1β 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.
| Original language | English (US) |
|---|---|
| Article number | R21 |
| Journal | Breast Cancer Research |
| Volume | 11 |
| Issue number | 2 |
| DOIs | |
| State | Published - Apr 24 2009 |
Bibliographical note
Funding Information:We would like to thank Dr Jeff Rosen for providing reagents used in these studies, Dr Jim McCarthy for helpful discussions and use of densitometer, and Colleen Forster for help with tissue sectioning. In addition, we would like to acknowledge the use of the confocal microscope made available through an NCRR Shared Instrumentation Grant (#1 S10 RR16851). This work was supported in part by funds from the Masonic Cancer Center, University of Minnesota Translational Breast Cancer Award, the Minnesota Medical Foundation (#3800-9227-07), an American Cancer Society Institutional Research Grant (IRG #21) and a Susan G Komen for the Cure Career Catalyst Award (KG081326).
