Research article

Breast cancer-associated metastasis is significantly increased in a model of autoimmune arthritis

Lopamudra Das Roy^1,2 , Latha B Pathangey¹ , Teresa L Tinder^1,2 , Jorge L Schettini^1,2 , Helen E Gruber³ and Pinku Mukherjee^1,2

¹  Department of Immunology, Mayo Clinic School of Medicine, 13400 E. Shea Blvd., Scottsdale, Arizona-85259, USA

²  Department of Biology, University of North Carolina at Charlotte, 9201 University City Blvd., Charlotte, NC-28223, USA

³  Department of Orthopedic Surgery, Carolinas Medical Center, 1543 Garden Terrace, Charlotte, NC-28232, USA

author email corresponding author email

Breast Cancer Research 2009, 11:R56doi:10.1186/bcr2345

Published:	30 July 2009

Abstract

Introduction

Sites of chronic inflammation are often associated with the establishment and growth of various malignancies including breast cancer. A common inflammatory condition in humans is autoimmune arthritis (AA) that causes inflammation and deformity of the joints. Other systemic effects associated with arthritis include increased cellular infiltration and inflammation of the lungs. Several studies have reported statistically significant risk ratios between AA and breast cancer. Despite this knowledge, available for a decade, it has never been questioned if the site of chronic inflammation linked to AA creates a milieu that attracts tumor cells to home and grow in the inflamed bones and lungs which are frequent sites of breast cancer metastasis.

Methods

To determine if chronic inflammation induced by autoimmune arthritis contributes to increased breast cancer-associated metastasis, we generated mammary gland tumors in SKG mice that were genetically prone to develop AA. Two breast cancer cell lines, one highly metastatic (4T1) and the other non-metastatic (TUBO) were used to generate the tumors in the mammary fat pad. Lung and bone metastasis and the associated inflammatory milieu were evaluated in the arthritic versus the non-arthritic mice.

Results

We report a three-fold increase in lung metastasis and a significant increase in the incidence of bone metastasis in the pro-arthritic and arthritic mice compared to non-arthritic control mice. We also report that the metastatic breast cancer cells augment the severity of arthritis resulting in a vicious cycle that increases both bone destruction and metastasis. Enhanced neutrophilic and granulocytic infiltration in lungs and bone of the pro-arthritic and arthritic mice and subsequent increase in circulating levels of proinflammatory cytokines, such as macrophage colony stimulating factor (M-CSF), interleukin-17 (IL-17), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-alpha) may contribute to the increased metastasis. Treatment with anti-IL17 + celecoxib, an anti-inflammatory drug completely abrogated the development of metastasis and significantly reduced the primary tumor burden.

Conclusions

The data clearly has important clinical implications for patients diagnosed with metastatic breast cancer, especially with regards to the prognosis and treatment options.