Oestrogen receptor negative breast cancers exhibit high cytokine content

Abstract

Introduction

An emerging hypothesis suggests that cytokines could play an important role in cancer as potential modulators of angiogenesis and leucocyte infiltration.

Methods

A novel multiplexed flow cytometry technology was used to measure the expression of 17 cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 [p70], IL-13, IL-17, granulocyte colony-stimulating factor [CSF], granulocyte-macrophage CSF, IFN-γ, monocyte chemoattractant protein [MCP]-1, macrophage inflammatory protein [MIP]-1β, tumour necrosis factor [TNF]-α) at the protein level in 105 breast carcinoma. B lymphocyte, T lymphocyte and macrophage levels were determined by immunohistochemistry.

Results

Fourteen of the 17 cytokines were expressed in breast carcinoma, whereas only nine cytokines could be detected in normal breast. Most cytokines were more abundant in breast carcinoma than in normal breast, with IL-6, IL-8, granulocyte CSF, IFN-γ, MCP-1 and MIP-1β being very abundant. IL-2, IL-6, IL-8, IL-10, IFN-γ, MCP-1, MIP-1β and TNF-α, and to a lesser extent IL-1β and IL-13 exhibited levels of expression that were inversely correlated to oestrogen receptor and progesterone receptor status. Most cytokines were not correlated with age at cancer diagnosis, tumour size, histological type, or lymph node status. However, IL-1β, IL-6, IL-8, IL-10, IL-12, MCP-1 and MIP-1β were more abundant in high-grade tumours than in low-grade tumours. In addition, IL-8 and MIP-1β were expressed to a greater degree in HER2-positive than in HER2-negative patients. The expression of most of the studied cytokines was correlated to levels of activator protein-1, which is known to regulate numerous cytokines. Overexpression of MCP-1 and MIP-1β were linked to B lymphocyte, T lymphocyte and macrophage infiltration, whereas high levels of IL-8 were correlated with high macrophage content in tumour. Moreover, IL-8 positive tumours exhibited increased vascularization.

Conclusion

We found that multiple cytokines were overexpressed in oestrogen receptor negative breast carcinoma, and that the three major cytokines – MCP-1, MIP-1β and IL-8 – were correlated with inflammatory cell component, which could account for the aggressiveness of these tumours.