Tumor-associated macrophages play a critical role in
breast tumor progression; however, it is still unclear what effector molecular mechanisms they employ to impact
tumorigenesis.
Ferritin is the primary intracellular
iron storage
protein and is also abundant in circulation. In
breast cancer patients,
ferritin is detected at higher levels in both serum and
tumor lysates, and its increase correlates with poor clinical outcome. In this study, we comprehensively examined the distribution of
ferritin in normal and malignant breast tissue at different stages in
tumor development. Decreased
ferritin expression in
cancer cells but increased infiltration of
ferritin-rich CD68-positive macrophages was observed with increased
tumor histological grade. Interestingly,
ferritin stained within the stroma surrounding
tumors suggesting local release within the breast. In cell culture, macrophages, but not
breast cancer cells, were capable of
ferritin secretion, and this secretion was further increased in response to pro-inflammatory
cytokines. We next examined the possible functional significance of extracellular
ferritin in a
breast cancer cell culture model.
Ferritin stimulated the proliferation of the epithelial
breast cancer cell lines MCF7 and T47D. Moreover, this proliferative effect was independent of the
iron content of
ferritin and did not increase intracellular
iron levels in
cancer cells indicating a novel
iron-independent function for this
protein. Together, these findings suggest that the release of
ferritin by infiltrating macrophages in
breast tumors may represent an inflammatory effector mechanism by which
ferritin directly stimulates
tumorigenesis.