Abstract 3253: Bone morphogenetic proteins increase hepcidin in breast cancer cells

Abstract Hepcidin is a systemic peptide hormone produced in the liver that regulates iron absorption and recirculation. Induction of hepcidin by inflammatory cytokines has been suggested to contribute to the anemia of inflammation and cancer. Our previous work has shown that synthesis of hepcidin is not confined to the liver, but is also observed in other tissues. In particular, we found that hepcidin is produced in mammary epithelial cells. Further, hepcidin levels increase in a subset of breast cancers, and increased synthesis of hepcidin is associated with poor prognoses in some breast cancer patients (Pinnix et al., 2010). In this work we sought to understand mechanisms regulating hepcidin synthesis in breast cancer, as well as the consequences of hepcidin upregulation. We demonstrate that treatment with bone morphogenetic proteins (BMPs) 2, 4, 6, or 7 results in hepcidin upregulation and concomitant Smad phosphorylation in breast cancer cells. The BMP7-induced hepcidin increase can be diminished by co-treatment of breast cancer cells with the BMP inhibitors, Wise or Noggin. We next assessed the consequence of hepcidin induction. Systemic hepcidin regulates iron by affecting the levels of the iron export protein, ferroportin. Extracellular hepcidin binds to ferroportin on the cell surface, initiating the internalization and degradation of ferroportin. This, in turn, decreases the ferroportin available to facilitate iron export, preventing iron efflux from the cell and increasing cellular iron retention. To test the functionality of this regulatory pathway in breast cancer, we used a hepcidin-specific antibody to deplete cultured breast cancer cells of extracellular hepcidin. We found that antibody-induced hepcidin depletion increased ferroportin protein levels, suggesting that hepcidin-mediated ferroportin regulation occurs in breast cancer cells. Consistent with this finding, we observed that breast cancer cells have increased hepcidin and decreased ferroportin relative to normal mammary epithelial cells. In all, these results raise the possibility that BMP signaling may control hepcidin expression in breast cells, decreasing ferroportin and increasing intracellular iron. The potential for hepcidin to alter iron availability to breast cancer cells on a paracrine level is a novel function for this key systemic iron regulator. Reference Z. K. Pinnix, L. D. Miller, W. Wang, R. D'Agostino Jr., T. Kute, M. C. Willingham, H. Hatcher, L. Tesfay, G. Sui, X. Di, S. V. Torti, F. M. Torti, Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis. Sci. Transl. Med. 2, 43ra56 (2010). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3253. doi:1538-7445.AM2012-3253