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.
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 197, Tuesday Afternoon