Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer

Abstract

Germ-line mutations in PALB2 lead to a familial predisposition to breast and pancreatic cancer or to Fanconi Anemia subtype N. PALB2 performs its tumor suppressor role, at least in part, by supporting homologous recombination-type double strand break repair (HR-DSBR) through physical interactions with BRCA1, BRCA2, and RAD51. To further understand the mechanisms underlying PALB2-mediated DNA repair and tumor suppression functions, we targeted Palb2 in the mouse. Palb2-deficient murine ES cells recapitulated DNA damage defects caused by PALB2 depletion in human cells, and germline deletion of Palb2 led to early embryonic lethality. Somatic deletion of Palb2 driven by K14-Cre led to mammary tumor formation with long latency. Codeletion of both Palb2 and Tumor protein 53 (Trp53) accelerated mammary tumor formation. Like BRCA1 and BRCA2 mutant breast cancers, these tumors were defective in RAD51 focus formation, reflecting a defect in Palb2 HR-DSBR function, a strongly suspected contributor to Brca1, Brca2, and Palb2 mammary tumor development. However, unlike the case of Brca1-mutant cells, Trp53bp1 deletion failed to rescue the genomic instability of Palb2-or Brca2-mutant primary lymphocytes. Therefore, Palb2-driven DNA damage control is, in part, distinct from that executed by Brca1 and more similar to that of Brca2. The mechanisms underlying Palb2 mammary tumor suppression functions can now be explored genetically in vivo.mouse model | familial breast cancer

PALB2: The hub of a network of tumor suppressors involved in DNA damage responses

“…The PALB2 network is thought to suppress tumor formation by promoting DNA repair, thereby preventing genome instability and the initiation of cancer. Consistent with this thinking, BRCA1, PALB2, BRCA2, and RAD51C all prevent chromosome instability characterized by chromosome breaks or rearrangements that occur spontaneously, or in response to DNA interstrand crosslinking agents or PARP inhibitors [21, 26, 30, 81, 142]. …”

Male Fertility Defect Associated with Disrupted BRCA1-PALB2 Interaction in Mice

“…CC6 Knockin Strain-The targeting construct was based on an existing conditional knock-out construct recently described (23). The construct contains loxP sites flanking exons 2 and 3 of the mouse Palb2 gene.…”

“…The final strain contains the knockin mutation along with two loxP sites and one Frt site on a mixed 129/B6 background. Genotyping was conducted as described (23). All mouse work was approved by the Institutional Animal Care and Use Committee (IACUC) of the Rutgers Robert Wood Johnson Medical School ( New Brunswick, NJ) under the protocol numbers I08-073-9 and I11-029-5.…”

“…Similar to Brca1 and Brca2, systemic knock-out of Palb2 leads to early embryonic lethality (21)(22)(23), and conditional ablation in the mammary gland results in breast cancer devel-opment (23,24). To circumvent the embryonic lethality of complete Palb2 knock-out and further study PALB2 function in vivo, we generated a knockin mutation in the N terminus of mouse PALB2 that abrogates its interaction with BRCA1.…”

Understanding the role of the MYB oncogene in human breast cancer: targets and functions

“…Accumulation of DNA damage and DNA repair defects such as BRCA1 (Cressman et al, 1999, Cipollini et al, 2004, BRCA2 (Walsh et al, 2006) or PALB2 (Bowman-Colin et al, 2013) are intimately related to breast cancer. Several DNA damage response genes were identified as MYB target genes by ChIP studies (Quintana et al, 2011).…”