Abstract
Abstract Objective: Psoriasin (S100A7), small 11 kDa calcium binding protein, has been shown to be highly expressed in ER-alpha-negative (ERα−) invasive breast carcinomas with poor patient outcome. However, the role of S100A7 in breast cancer progression and metastasis is not well understood. Here we elucidate S100A7-mediated effects in breast tumorogenesis. Methods: We studied EGF-mediated cell migration and cell motility in vitro in S100A7 overexpressing MDA-MB-231 (231-S100A7) cells by standard assays. We generated bi-transgenic MMTV-rtTA; mS100A7/A15 mice which expressed mS100A7/A15 in mammary glands under doxycycline (Dox) (1g/kg) treatment. Mammary glands were isolated and stained for carmine, H&E and immunostaining according to the standard protocols. We also injected MVT1 cells (derived from MMTV-c-Myc; MMTV-VEGF) orthotopically into the mammary glands of bi-transgenic mice to study the role of mS100A7/A15 in mammary tumor growth and metastasis. Results: In the present investigation, we have shown that S100A7 overexpression in ERα− breast cancer cell line enhanced EGF-induced migration and wound healing compared to vector control cells. Further elucidation of signaling mechanisms reveal that S100A7 enhanced EGF-induced EGFR and Stat3 activation. Microarray and real time PCR analysis revealed upregulation of pro-inflammatory molecules such as CXCL8, CXCL1, IL-1α, serum amyloid A2 (SAA2) and MMP9 in 231-S100A7 cells compared to 231-Vec. These results were further confirmed with cytokine array analysis in the conditioned media (CM) of 231-S100A7 cells compared to 231-Vec. To further characterize the role of S100A7, we targeted the expression of murine homologue of S100A7, also known as mS100A7/A15, to mammary epithelial cells by generating bi-transgenic MMTV-rtTA; mS100A7/A15 mice. Morphological examination of the mammary glands after three months of Dox treatment revealed ductal hyperplasia, enhanced mS100A7/A15, Ki67 and cyclin D1 expression compared to uninduced mice. We also showed enhanced activation of Stat3, AKT, ERK1/2, MMP2 and SAA2 in the mammary glands of these mice. We further observed enhanced tumor growth and metastasis of orthotopically injected MVT1 cells in Dox treated compared to untreated mice. Tumors and lung tissues obtained from Dox treated bi-transgenic mice showed increased expression of prometastatic genes and enhanced recruitment of tumor-associated macrophages (TAM). Furthermore, CM from 231-S100A7 cells significantly enhanced migration of THP1-differentiated macrophages. Conclusion: These findings suggest that S100A7 may regulate breast cancer progression and metastasis by enhancing inflammatory signals that result in enhanced recruitment of TAM. Furthermore, these studies suggest that S100A7 is a novel therapeutic target for the treatment of breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 403. doi:10.1158/1538-7445.AM2011-403
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