Abstract 445: Coordinate loss of CHD1 and MAP3K7 promotes aggressive prostate cancer

Abstract

Abstract The genomic complexity of prostate cancer contributes to disease progression, resistance to therapy, and development of metastases. The genes CHD1 and MAP3K7 are signficantly co-deleted in 10-15% of primary tumors and combined loss of CHD1 and MAP3K7 expression is associated with poor disease-free survival. We recently validated MAP3K7 as a prostate tumor suppressor, but CHD1's role in prostate tumorigenesis has not been evaluated. In this study, we used a mouse prostate epithelial stem cell (PrP/SC) model and a human prostate cancer cell line (LNCaP) model to investigate how loss of CHD1 alone or in combination with MAP3K7 suppression affects prostate tumorigenesis. Suppression of Map3k7 increased proliferation of PrP/SCs. Chd1 suppression decreased growth of wildtype PrP/SCs but not PrP/SCs already deficient in Map3k7 expression. Similarly, suppression of CHD1 in LNCaP cells decreased proliferation when MAP3K7 expression was present, but not when MAP3K7 was suppressed. These data suggest that loss of CHD1 alone is deleterious to growth, but that MAP3K7 suppression can compensate for this growth inhibition. Chd1 and Map3k7-deficient PrP/SCs were then evaluated in vivo using tissue recombination. When Chd1-deficient PrP/SCs were recombined with fetal rat urogenital mesenchyme (rUGM) and implanted under the renal capsules of immunocompromised mice, grafts contained mostly benign glandular tissue with focal areas of mild hyperplasia/prostatic intraepithelial neoplasia (PIN). A few nuclear abnormalities were observed. Map3k7-deficient recombinants generated a mixture of benign tissue, PIN, and adenocarcinoma (consistent with our previous findings). The nuclear morphology of these grafts was unremarkable. Strikingly, dual Chd1-Map3k7 knockdown recombinants displayed massive glandular atypia with glands completely filled with AR-negative and p63-negative cells. These cells had large nuclei, prominent nucleoli, and abundant cytoplasm. Tumorigenicity of CHD1 and/or MAP3K7-deficient LNCaP cells was also assessed by subcutaneous implantation of cells into immunocompromised mice. Mice implanted with CHD1-deficient xenografts formed smaller tumors and had increased survival relative to mice injected with control LNCaP cells (p=0.0083). MAP3K7-deficient xenografts were similar in size and in survival rate compared to control LNCAP cells. Dual CHD1-MAP3K7 deficient xenografts, in contrast, showed increased tumor growth and decreased survival relative to control (p=0.0242), MAP3K7 alone (p=0.0462) and CHD1 alone (p=0.0002). Collectively, these data suggest that loss of CHD1 alone is anti-tumorigenic but that combined loss of CHD1 and MAP3K7 drives aggressive prostate cancer development. Citation Format: Lindsey Ulkus, Leah Rider, Cera Nieto, Lina Romero, Haitao Chen, Massimo Loda, Wennuan Liu, Jianfeng Xu, Scott Cramer. Coordinate loss of CHD1 and MAP3K7 promotes aggressive prostate cancer. [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 445. doi:10.1158/1538-7445.AM2014-445