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

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

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.

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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

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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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  1. Molecular Biotechnology Center and Department of Genetics, Biology and Biochemistry, University of Turin, Via Nizza 52, 10126, Turin, Italy

    Sara Pensa & Valeria Poli

  2. Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Christine J. Watson

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  1. Sara Pensa
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Correspondence to Christine J. Watson.

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Pensa, S., Watson, C.J. & Poli, V. Stat3 and the Inflammation/Acute Phase Response in Involution and Breast Cancer. J Mammary Gland Biol Neoplasia 14, 121–129 (2009). https://doi.org/10.1007/s10911-009-9124-x

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