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Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA
Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
* Author to whom correspondence should be addressed.
Received: 16 January 2013; in revised form: 25 January 2013 / Accepted: 28 January 2013 / Published: 1 February 2013
Abstract: Approximately 25,000 ovarian cancers are diagnosed in the U.S. annually, and 75% are in the advanced stage and largely incurable. There is critical need for early detection tools and novel treatments. Proteasomal ubiquitin receptor ADRM1 is a protein that is encoded by the ADRM1 gene. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. Its overexpression correlated significantly with shorter time to recurrence and overall survival. Array-CGH and microarray expression of ovarian cancer cell lines provided evidence consistent with primary tumor data that ADRM1 is a 20q13 amplification target. Herein, we confirm the ADRM1 amplicon in a second ovarian cancer cohort and define a minimally amplified region of 262 KB encompassing seven genes. Additionally, using RNAi knock-down of ADRM1 in naturally amplified cell line OAW42 and overexpression of ADRM1 via transfection in ES2, we show that (1) ADRM1 overexpression increases proliferation, migration, and growth in soft agar, and (2) knock-down of ADRM1 results in apoptosis. Proteomic analysis of cells with ADRM1 knock-down reveals dysregulation of proteins including CDK-activating kinase assembly factor MAT1. Taken together, the results indicate that amplified ADRM1 is involved in cell proliferation, migration and survival in ovarian cancer cells, supporting a role as an oncogene and novel therapeutic target for ovarian cancer.
Keywords: ADRM1; oncogene; ovarian cancer
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Fejzo, M.S.; Anderson, L.; von Euw, E.M.; Kalous, O.; Avliyakulov, N.K.; Haykinson, M.J.; Konecny, G.E.; Finn, R.S.; Slamon, D.J. Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer. Int. J. Mol. Sci. 2013, 14, 3094-3109.
Fejzo MS, Anderson L, von Euw EM, Kalous O, Avliyakulov NK, Haykinson MJ, Konecny GE, Finn RS, Slamon DJ. Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer. International Journal of Molecular Sciences. 2013; 14(2):3094-3109.
Fejzo, Marlena S.; Anderson, Lee; von Euw, Erika M.; Kalous, Ondrej; Avliyakulov, Nuraly K.; Haykinson, Michael J.; Konecny, Gottfried E.; Finn, Richard S.; Slamon, Dennis J. 2013. "Amplification Target ADRM1: Role as an Oncogene and Therapeutic Target for Ovarian Cancer." Int. J. Mol. Sci. 14, no. 2: 3094-3109.