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Stat3 and the Inflammation/Acute Phase Response in Involution and Breast Cancer

  • Sara Pensa
  • Christine J. WatsonEmail author
  • Valeria Poli
Article

Abstract

The transcription factor Stat3 is essential for timely initiation of post-lactational regression and orchestrates the processes of cell death and tissue remodelling that occur during the first 6 days of involution in the mouse. Paradoxically, STAT3 is also frequently found to be constitutively active in breast cancer and tumors can become addicted to STAT3. This raises two interesting questions: 1) do the high levels of active Stat3 present in the mammary epithelium during involution promote tumor spread and 2) how do tumor cells escape the pro-apoptotic effects of Stat3? In order to address these questions, it is essential to understand the role of Stat3 in involution and the mechanisms by which Stat3 regulates both cell death and tissue remodelling. A number of studies have been undertaken using genetically modified mice and microarray analyses and two significant findings arose from these investigations. Firstly, post-lactational regression is associated with an acute phase and inflammatory response in addition to cell death and secondly, Stat3 alone is insufficient to induce involution in the absence of the NF-κB regulatory kinase IKKβ. Both Stat3 and NF-κB have been shown to regulate the expression of genes involved in inflammatory signalling and the acute phase response. These findings suggest a role for the innate immune response in mammary epithelial cell fate during involution and highlight potential roles for this response in tissue remodelling-associated breast cancer metastasis.

Keywords

Stat3 Mammary gland Apoptosis Acute phase response Inflammation Breast cancer 

Abbreviations

Stat

Signal transducer and activator of transcription

APR

acute phase response

APRF

acute phase response factor

APP

acute phase protein

AIR

anti-inflammatory response

IEC

intestinal epithelial cells

DSS

dextran sodium sulfate

AOM

azoxymethane

APC

antigen presenting cell

TAM

tumor associated macrophage

DC

dendritic cells

Treg

regulatory T cell

Th

T helper

EMT

epithelial to mesenchymal transition

OSMR

oncostatin M receptor

ORM

orosomucoid

CRP

C-reactive protein

SAA

serum amyloid A

c/ebp

CAAT-enhancer binding protein

Slpi

secretory leukocyte protease inhibitor

Notes

Acknowledgements

The authors’ laboratories are funded by the Italian Cancer Research Association (AIRC), the Italian Ministery for University and Research (MIUR) COFIN and FIRB, the Progetto Alfieri (Fondazione CRT), the Biotechnology and Biological Sciences Research Council, the Association for International Cancer Research, The Wellcome Trust and the Breast Cancer Campaign.

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Sara Pensa
    • 1
  • Christine J. Watson
    • 2
    Email author
  • Valeria Poli
    • 1
  1. 1.Molecular Biotechnology Center and Department of Genetics, Biology and BiochemistryUniversity of TurinTurinItaly
  2. 2.Department of PathologyUniversity of CambridgeCambridgeUK

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