Poster Presentation 25th Lorne Cancer Conference 2013

Tumour manifestation is dictated by PML in a gender-specific manner in a mutant p53 cancer model (#201)

Sue Haupt 1 , Vincent Corneille 1 , Catherine Mitchell 1 , Jake Shortt 1 , Stephen Fox 1 , Daniel Buckley 1 , Pier Paolo Pandolfi 2 , Mireia Castillo-Martin 3 , Dennis Bonai 3 , Carlos Cordon-Carlo 3 , Guillermina Lozano 4 , Ygal Haupt 1
  1. Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia
  2. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
  3. Mount Sinai School of Medicine, New York, NY 10029, USA
  4. MD Anderson Cancer Center, The Universty of Texas, Houston, TX 77030, USA

The contribution of PML to tumor suppression was evaluated in a spontaneous mouse cancer model, in which a germ line mutation in the p53 gene (p53R172H) recapitulates a human hotspot mutation common in human sporadic and Li-Fraumeni cancers (p53R175H). In this study, we demonstrated that the complete absence of PML from p53wild type/R172H (p53+/R172H) heterozygous mice, but not mutant homozygous mice, reduced survival and influenced tumor manifestation. Strikingly, these phenomena were most pronounced for male mice, suggesting a gender bias for PML influence. Explicitly, p53+/R172H male mice lacking PML developed soft tissue sarcomas that were associated with reduced survival. In the absence of PML, tumors developed in p53+/R172H mice with elevated p53 levels, associated with enhanced levels of the oncogenic activation associated protein p19Arf. Together, these findings suggest that PML is an important tumor suppressor in a germ line ­mutant p53 mouse model of human cancer.