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Alterations of the  PALB2  tumor suppressor gene have been identified in familial breast, ovarian and pancreatic cancer cases. PALB2 cooperates with BRCA1/2 proteins through physical interaction in initiation of homologous recombination, in maintenance of genome integrity following DNA double-strand breaks. To determine if the role of PALB2 as a linker between BRCA1 and BRCA2 is critical for BRCA1/2-mediated tumor suppression, we generated  Palb2  mouse pancreatic cancer models and compared tumor latencies, phenotypes and drug responses with previously generated  Brca1/2  pancreatic cancer models. For development of  Palb2  pancreatic cancer, we crossed conditional  Palb2  null mouse with mice carrying the  Kras   G12D   ; p53   R270H   ; Pdx1-Cre  ( KPC ) constructs, and these animals were observed for pancreatic tumor development. Individual deletion of  Palb2 ,  Brca1  or  Brca2  genes in pancreas  per se  using  Pdx1-Cre  was insufficient to cause tumors, but it reduced pancreata size. Concurrent expression of mutant  Kras   G12D   and  p53   R270H  , with tumor suppressor inactivated strains in  Palb2 - KPC ,  Brca1 - KPC  or  Brca2 - KPC , accelerated pancreatic ductal adenocarcinoma (PDAC) development. Moreover, most  Brca1 - KPC  and some  Palb2 - KPC  animals developed mucinous cystic neoplasms with PDAC, while  Brca2 - KPC  and  KPC  animals did not. 26% of  Palb2- KPC mice developed MCNs in pancreata, which resemble closely the  Brca1  deficient tumors. However, the remaining 74% of  Palb2-KPC  animals developed PDACs without any cysts like  Brca2  deficient tumors. In addition, the number of ADM lesions and immune cells infiltrations (CD3 +  and F/480 + ) were significantly increased in  Brca1-KPC  tumors, but not in  Brca2-KPC  tumors. Interestingly, the level of ADM lesions and infiltration of CD3 +  or F/480 +  cells in  Palb2-KPC  tumors were intermediate between  Brca1-KPC  and  Brca2-KPC  tumors. As expected, disruption of  Palb2  and  Brca1 /2 sensitized tumor cells to DNA damaging agents  in vitro  and  in vivo . Altogether,  Palb2 - KPC  PDAC exhibited features observed in both  Brca1 - KPC  and  Brca2 - KPC  tumors, which could be due to its role, as a linker between Brca1 and Brca2.

plos one

Murine models for familial pancreatic cancer: Histopathology, latency and drug sensitivity among cancers of Palb2, Brca1 and Brca2 mutant mouse strains