ABSTRACT: INTRODUCTION: Breast cancer remains the second leading cause of cancer related deaths for women in the United States. Metastasis is regulated not only by intrinsic genetic changes in malignant cells, but also by the microenvironment, especially those associated with chronic inflammation. We have recently reported that mice that suffer from autoimmune arthritis have significantly increased incidence of bone and lung metastasis and decreased survival associated with breast cancer. In this study, we evaluated the mechanism underlying the increased metastasis. Methods We used two mouse models; one that develops spontaneous autoimmune arthritis (SKG mice) injected with metastatic breast cancer cells (4T1), and second, that develops spontaneous breast cancer (MMTV-PyV MT mice) injected with type II collagen to induce autoimmune arthritis. Mast cell levels and metastasis were monitored. RESULTS: First, we confirm that breast tumor-bearing arthritic mice have significantly higher incidence of bone and lung metastasis than their non-arthritic counterparts. Next, we show increased recruitment of mast cells within the primary tumor of arthritic mice which facilitate metastasis. Next, we report that arthritic mice without any tumors have higher numbers of mast cells in the bones and lungs which may be the underlying cause for the enhanced lung and bone metastasis observed in the arthritic mice. Next, we show that once the tumor cells populate the metastatic niches (bones and lungs), they further increase the mast cell population within the niche and assist in enhancing metastasis. This may primarily be due to the interaction of c-kit receptor present on mast cells and stem cell factor (SCF, the ligand for ckit) expressed on tumor cells. Finally, we show that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis. CONCLUSION: This is the first report to show that mast cells may play a critical role in not only remodeling the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.
Breast cancer research: BCR 04/2013; 15(2):R32. · 5.24 Impact Factor