OR26-5 COPY NUMBER AMPLIFICATION AND OVEREXPRESSION OF MAMMALIAN STERILE20-LIKE KINASE 4 (MST4) IN PITUITARY TUMORS: A NOVEL THERAPEUTIC TARGET

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR26-Pituitary Tumorigenesis: Advances in Mechanism & Treatment
Translational
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 130 (Moscone Center)
Margaret E Wierman*1, Mei Xu2, Maozhen Tian2, Katja Kiseljak-Vassiliades2, Aaron James Knox2, Michael Edwards2, Bette Kleinschmidt-Demasters2, Mark Geraci2 and Kevin Lillehei2
1University of Colorado Denver and Research Service VAMC, Aurora, CO, 2University of Colorado Denver, Aurora, CO
The genetic and molecular mechanisms which initiate or promote the growth of pituitary tumors are poorly understood. To identify novel tumor candidate genes and pathways we used a combined approach, integrating data from expression microarrays with whole-genome screens for copy number alterations (CNA). Candidate genes with both aberrant expression and overlapping CNAs in tumors were characterized further. A microarray screen (Human U133Plus2.0) compared the gene expression profiles of 14 gonadotrope lineage tumors versus 9 normal pituitaries from autopsy using an ANOVA model to identify significantly altered genes. To detect gene amplifications and deletions, a microarray-based copy number screen was performed on Genome-Wide Human SNP 6.0 Arrays in 10 gonadotrope tumors. CNAs were assessed using 794 HapMap samples as the baseline genomes and segmentation analysis. Mammalian Sterile20-like kinase (MST4) transcript was increased 6.3-fold in tumors compared to normal pituitary and located within 390 kb amplification at Xq26.2 in one tumor sample from a female patient. A second predicted gene, LOC286467, was also within the Xq26.2 amplification; however, the transcript was undetectable in normal or tumor. MST4 is a serine-threonine kinase, whose upstream regulators and downstream effectors are poorly defined. MST4 recently has been suggested to direct cell specific anchorage independent growth, in vitro proliferation, cell migration, and in vivo tumorigenesis.  Immunoblot and immunohistochemistry demonstrated MST4 protein is undetectable in human pituitary and consistently upregulated in a variety of human pituitary tumors.  Stable overexpression of MST4 in LβT2 cells created a model to explore the functional effects of MST4. MST4 cells demonstrated increased rates of proliferation (1.4 fold) compared to vector control and were tumorigenic (3.4 fold) in a soft agar assay. Although unresponsive to growth factor withdrawal, MST4 cells were protected from oxidative stress (H2O2) and hypoxia-induced cell death through activation of PI3K/Akt and p38MAPK pathways. Thus MST4, identified by dual screening approaches, is a novel kinase upregulated in human pituitary tumors. Further investigation of its pituitary specific upstream activators and downstream targets may reveal novel pathways underlying pituitary tumorigenesis.  In addition, the MST4 kinase is a novel potential therapeutic target.

Nothing to Disclose: MEW, MX, MT, KK, AJK, ME, BK, MG, KL

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Funded by VA Merit Review to MEW, UCD Cancer Center and Genomics Core