Abstract 3286: Interleukin-17 receptor c (IL-17RC) knockout mice developed fewer and smaller prostate tumors compared to the wild-type mice in Pten-deficient context

Abstract

Abstract Introduction: Interleukinα17 (ILα17) is a key cytokine in inflammatory and immune diseases. ILα17 may promote or inhibit tumor growth. Several studies have linked ILα17 with prostate cancer. ILα17's role in prostate cancer is unknown. The objective of this study is to investigate ILα17's role in formation and growth of prostate adenocarcinoma. Methods: ILα17 receptor C (ILα17RC) knockout mice were crossed with Pten conditional knockout mice (using ProbasinαCre). Ptenα/β male mice with intact ILα17 signaling (named RC+ mice, including ILα17RC+/+ and ILα17RC+/−) were compared with Ptenα/β male mice without ILα17 signaling (ILα17RCα/α, named RCβ mice). Results: There was no difference between the weight of genitourinary bloc of RC+ mice and that of RCβ mice at 4, 6 and 9 weeks. At 12 and 30 weeks, the GUαbloc weight of RC+ mice was 14% and 47% heavier than that of RCβ mice, respectively (P = 0.005, N = 54, and P = 0.004, N = 32, respectively). We found similar prostatic epithelial hyperplasia at 4 weeks and prostatic intraepithelial neoplasia (PIN) at 6 weeks in both RC+ and RCβ mice, suggesting that ILα17RC knockout did not affect PIN formation. At 9 weeks, invasive cancer was formed in 87% of RC+ prostate lobes, but only in 25% of RCβ prostate lobes (P < 0.001). At 30 weeks, 100% of RC+ prostate lobes formed invasive cancer, whereas only 70% of RCβ prostate lobes showed invasive cancer (P < 0.005). This suggests that ILα17RC knockout decreased progression of PIN to invasive cancer. The RCβ PINs were surrounded with a thick layer of fibromuscular stroma, whereas the stroma layer was significantly thinner in RC+ prostate glands, suggesting that failure of PIN to invade stroma was a critical deficit in RCβ mice. We found that MMP7 expression was significantly decreased in RCβ prostates compared to RC+ prostates, suggesting that lack of MMP7 expression is likely responsible for the observed phenotype. Furthermore, we found that ILα17 treatment induced MMP7 mRNA and protein expression in exαvivo cultured RC+ prostate tissues but not in RCβ prostate tissues, suggesting that MMP7 is a downstream target gene of ILα17 signaling. Conclusions: ILα17 promotes prostate adenocarcinoma formation and growth through induction of MMP7 expression in mouse prostate. Funding provided by NIH/NCRR COBRE Grant (2P20RR020152α06), DoD (W81XWHα05α1α0567 and W81XWHα10α1α0937), Tulane Cancer Center, Louisiana Cancer Research Consortium, and Tulane Framework for Global Health Seed Grant. 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 3286. doi:1538-7445.AM2012-3286