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

Johanna R. Reed, Ronald P. Leon, Majken K. Hall, Kathryn L. Schwertfeger

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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 languageEnglish (US)
Article numberR21
JournalBreast Cancer Research
Volume11
Issue number2
DOIs
StatePublished - Apr 24 2009

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Receptor, Fibroblast Growth Factor, Type 1
Cyclooxygenase 2
Interleukin-1beta
Breast
Interleukin-1
Mouse mammary tumor virus
Human Mammary Glands
Epithelial Cells
Transgenic Mice
Breast Neoplasms
Tumor Microenvironment
Growth Factor Receptors
Transgenes
Hyperplasia

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Interleukin-1beta and fibroblast growth factor receptor 1 cooperate to induce cyclooxygenase-2 during early mammary tumourigenesis. / Reed, Johanna R.; Leon, Ronald P.; Hall, Majken K.; Schwertfeger, Kathryn L.

In: Breast Cancer Research, Vol. 11, No. 2, R21, 24.04.2009.

Research output: Contribution to journalArticle

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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.",
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AB - 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.

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