Abstract
Abstract Mammary carcinoma cells produce various growth factors that stimulate endothelial cells to promote angiogenesis in mammary carcinoma. Trefoil Factor 3 (TFF3) is a small secreted protein which is involved in protection of the gastrointestinal tract against mucosal damage. Our laboratory has also previously identified TFF3 as an orthotopically expressed oncogene in mammary carcinoma and observed that TFF3 stimulated oncogenicity and invasiveness of mammary carcinoma cells. Several studies have reported a significant positive association between TFF3 protein expression and microvessel density. However, the potential functional role of TFF3 in mammary carcinoma angiogenesis has not been determined. Herein, we defined the functional effect of TFF3 secreted by mammary carcinoma cells on the behavior of endothelial cells in de novo tumor angiogenesis. We utilized MCF-7 and T47D cells as our in vitro models by stable forced expression of TFF3 or siRNA mediated depletion of TFF3 in these cell lines. The effect of TFF3 secreted from mammary carcinoma cells on human umbilical vein endothelial cells (HUVEC) was determined by using a co-culture transwell system, whereby HUVEC cells were co-cultured with mammary carcinoma cells. We demonstrated that TFF3 secreted from mammary carcinoma cells promoted HUVEC cells monolayer cell cycle progression and proliferation, survival, migration, invasion, and in vitro tubule formation. In a xenograft model, mammary carcinoma cells with forced expression of TFF3 produced tumors with increased microvessel density (CD31 and CD34) compared to tumors formed by control cells. Depletion of TFF3 in mammary carcinoma cells by siRNA or inhibition with anti-TFF3 polyclonal antibody significantly decreased HUVEC cells monolayer cell cycle progression and proliferation, migration, invasion, and in vitro tubule formation. Mechanistically, we observed that TFF3 increased IL-8 expression in mammary carcinoma cells with forced expression of TFF3. Depletion of IL-8 in mammary carcinoma cells by siRNA or inhibition with anti-IL8 monoclonal antibody significantly decreased migration, invasion, and in vitro tubule formation of HUVEC cells promoted by TFF3. Hence, TFF3 is a promoter of tumor angiogenesis, which may co-coordinate with the growth promoting and metastatic actions of TFF3 in mammary carcinoma to enhance tumor progression. Citation Format: Wai-Hoe Lau, Vijay Pandey, Xiangjun Kong, Arindam Banerjee, Tao Zhu, Peter E. Lobie. Trefoil factor 3 promotes angiogenesis in mammary carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1020. doi:10.1158/1538-7445.AM2014-1020
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