title: Arthritis augments breast cancer metastasis: role of mast cells and SCF/c-Kit signaling.
abstract: BACKGROUND
  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 recently reported that mice with 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 another 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 confirmed that breast tumor-bearing arthritic mice have a significantly higher incidence of bone and lung metastasis than do their nonarthritic counterparts. Next, we showed increased recruitment of mast cells within the primary tumor of arthritic mice, which facilitates 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 metastases observed in the arthritic mice. Next, we showed 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 showed that targeting the SCF/cKit interaction with an anti-ckit antibody reduces the differentiation of mast cells and consequently reduces metastasis.
  
  
  CONCLUSIONS
  This is the first report to show that mast cells may play a critical role in remodeling not only the tumor microenvironment but also the metastatic niche to facilitate efficient metastasis through SCF/cKit interaction in breast cancer with arthritis.
authors.forename: Lopamudra
authors.initials: L
authors.lastname: Das Roy
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Curry
authors.forename: Mahnaz
authors.initials: M
authors.lastname: Sahraei
authors.forename: Dahlia M
authors.initials: DM
authors.lastname: Besmer
authors.forename: Amritha
authors.initials: A
authors.lastname: Kidiyoor
authors.forename: Helen E
authors.initials: HE
authors.lastname: Gruber
authors.forename: Pinku
authors.initials: P
authors.lastname: Mukherjee
mesh_terms: D000818:Animals; D017209:Apoptosis; D001169:Arthritis, Experimental / Q000150:complications / Q000503:physiopathology*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary*; D001943:Breast Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000209:etiology / Q000378:metabolism / Q000556:secondary*; D008407:Mast Cells / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D012333:RNA, Messenger; D019089:Stem Cell Factor; D019009:Proto-Oncogene Proteins c-kit