Abstract 388: mS100a7a15 enhances mammary tumor growth and metastasis by recruiting tumor associated macrophages
Authors: Mohd W. Nasser, Zahida Qamri, Yadwinder S. Deol, Janani Ravi, Catherine A. Powell, Prashant Trikha, Reto A. Schwendener, Konstantin Shilo, Ronald Wolf, Stuart H. Yuspa, Ramesh K. Ganju
Journal: Cancer Research (2012)

Abstract mS100a7a15 is the murine ortholog of human S100A7 and S100A15 proteins. Both S100A7 and S100A15 have been shown to play an important role in breast cancer. S100A7 has been shown to be highly expressed in high grade ductal carcinoma in situ and invasive breast cancers. Its expression is also related to poor prognosis and associated with increased inflammatory infiltrates and various inflammatory disorders. However, the exact mechanism by which S100A7 or S100A15 enhances breast cancer growth is not known. In the present study, we determined the molecular mechanisms by which mS100a7a15 enhances growth by overexpressing mS100a7a15 in MDA-MB-231 cells. We showed that mS100a7a15 enhances expression of proinflammatory molecules CXCL1 and CXCL8. In addition, we observed that supernatants obtained from mS100a7a15 overexpressing cells enhanced chemotaxis of murine RAW264.7 macrophages. Further elucidation revealed that mS100a7/a15 mediates its effects by binding to receptor for advanced glycation end products (RAGE). We further analyzed the role of mS100a7a15 on modulation of tumor growth and inflammatory pathways in breast cancer by generating inducible bi-transgenic MMTV-rtTA; mS100a7a15 mice (MMTV-mS100a7a15). These mice showed enhanced mS100a7a15 protein expression upon doxycycline treatment. Mammary glands isolated from these mice showed enhanced hyperplasia upon doxycycline treatment for 3 months compared to uninduced mice. Further studies revealed enhanced recruitment of macrophages in mammary glands and activation of STAT3 in induced mice. Orthotopic implantation of MVT-1 breast tumor cells (derived from MMTV-c-Myc; MMTV-VEGF mice) into the mammary glands of these mice showed enhanced tumor growth and metastasis in doxycycline treated mice compared to the control. Tumors and lung tissues obtained from these mice showed enhanced pro-metastatic gene expression and recruitment of F4/80 and CD206 positive M2 tumor-associated macrophages (TAM). However, no difference was observed in CD3+ and CD4+ T lymphocytes. Further elucidation of the role of macrophages by in vivo depletion of macrophages using clodronate liposomes revealed that mS100a7a15-mediated recruitment of TAM is important for tumor growth, angiogenesis and metastasis. Furthermore, mice treated with STAT3 inhibitors showed reduced mS100a7a15-induced hyperplasia. STAT3 has been shown to regulate expression of various inflammatory molecules. These studies using a novel mS100a7a15 bi-transgenic model system demonstrate that mS100a7a15 enhances breast tumor growth and metastasis by enhancing inflammatory signals that result in enhanced recruitment of TAM. 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 388. doi:1538-7445.AM2012-388