[1553] c-Jun Amplification and Overexpression Are Oncogenic in Liposarcoma but Not Sufficient To Inhibit Adipocytic Differentiation

EL Snyder, DJ Sandstrom, K Law, E Sicinska, M Loda, SJ Rodig, P Dal Cin, CDM Fletcher. Brigham and Women's Hospital, Boston, MA; Dana Farber Cancer Institute, Boston, MA

Background: The c-Jun proto-oncogene is amplified and overexpressed in dedifferentiated liposarcoma (DDLPS). c-Jun overexpression has been hypothesized to mediate the transition from well-differentiated liposarcoma (WDLPS) to DDLPS. However, we previously found that c-Jun is frequently expressed in the well-differentiated portions of DDLPS. We sought to further evaluate the role of c-Jun in liposarcoma by mapping the genomic location of the c-Jun amplicon in primary DDLPS and by performing functional studies with a cell line derived from a DDLPS with c-Jun amplification.
Design: We performed FISH for MDM2 and c-Jun on metaphase spreads from DDLPS samples with known c-Jun amplification. We also performed FISH for c-Jun on well-differentiated components of DDLPS with known c-Jun amplification. We derived a cell line (LP6) from a DDLPS with c-Jun amplification and infected the cells with lentivirus encoding shRNA to c-Jun or GFP as a negative control. We tested the effect of c-Jun knockdown on the ability of LP6 cells to grow in tissue culture and to form tumors in nude mice.
Results: We have identified a case of DDLPS in which the well-differentiated component exhibits high-level c-Jun amplification, suggesting that c-Jun amplification does not block adipocytic differentiation. When c-Jun is amplified in DDLPS, it is frequently interspersed with amplified MDM2 on ring and giant marker chromosomes, indicating that the two genes were amplified at the same time. c-Jun knockdown by two different shRNAs in LP6 cells reduces viable cell number in vitro. In nude mice, LP6 cells with stable c-Jun knockdown form tumors that are significantly smaller than control LP6 cells after subcutaneous injection. Tumors from c-Jun knockdown cells exhibit a lower Ki67 rate than controls, but c-Jun knockdown in LP6 cells does not result in the extensive lipid accumulation characteristic of WDLPS.
Conclusions: We propose that c-Jun amplification is oncogenic in liposarcomas, but frequently occurs at the same time as MDM2 amplification and does not directly inhibit adipocytic differentiation of the liposarcoma cells.
Category: Pathobiology

Tuesday, March 10, 2009 1:00 PM

Poster Session IV # 197, Tuesday Afternoon