Purpose: Hepatocellular Carcinoma (HCC) is one of the most malignant cancers worldwide. Due to the male prevalence of HCC, androgen signals have been suspected to be involved in the disease process. Although it has been known for the past five decades that androgens promote HCC progression, failure of antiandrogens in HCC clinical trials puzzled the field. Increasing evidences implied that androgen/AR signals might function differently during cancer progression. Therefore, it is necessary to examine the roles of AR in late stage HCC progression. Methods: Immunohistological staining on patient HCC tissues were performed. Using conditional knockout of AR specifically in the hepatocyte (h-ARKO), we characterized the pathophysiological function of AR in HCC. Cancer survival, pathological malignancy, and cancer metastasis was measured in the late stage of cancer development (40∼60-wks). Results: To our surprise, the h-ARKO mice exhibited poorer survival, malignant histological tumor patterns, and higher lung metastasis rates. Moreover, we found less collagen deposition, and higher cellular proteolysis activity in the h-ARKO mice tumors compared to wild type mice implicating invasive characteristic in the h-ARKO tumors. We further validated the mechanism that AR could suppress cancer progression through multiple pathways. We found AR functions as p38 phosphorylation suppressor while p38 phosphorylation increasing by cancer malignancy so that to obtain cell anoikis resistance. Therefore, androgen/AR signals enhance cell anoikis. We also found AR suppressed cancer cells invasion via suppression of MMP9 transcription. We further demonstrated that MMP9 suppression was through NFκB deactivation in the HCC cells. This is the first report that AR functions as cancer suppressor in late stage of cancer development. Furthermore, we demonstrated a potential application of this finding for HCC therapy. We introduced the combination therapy concept that using low doses of Sorafenib (multiple kinase inhibitor that pass clinical trials) and expression of AR in the HCC cells or metastasis mice model. It's exciting that AR could synergistically facilitate Sorafenib effects to increase cell anoikis and suppress cell invasion. Combination therapy in the mice metastasis model pertain more metastasis-free and better cancer survival in the mice. Conclusion: This study revealed the biphasic, yet, opposite functions of AR in HCC progression. It not only explained the failure of antiandrogen in HCC therapy, but also implicated a critical timing of using anti-Androgen/AR signals. Last, our hypothetical preclinical trial shed a light on future medicine for late stage HCC therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2917.