PALB2 mutations increase oncogenic properties of breast epithelial cells by enhancing JAM3 and PARVB expression.

High-risk genes, heterozygous pathogenic mutations of which predispose to familial breast cancers, typically encode factors securing a proper DNA damage response. PALB2 is one such major cellular factor that is needed for alleviation of genomic, replicative, and oxidative stresses. Thus, it has a crucial role in maintaining genomic integrity and protecting cells against cancer. While the malfunctions in DNA damage repair of PALB2-mutated cells have extensively been documented, our research continues to explore cells' other pro-tumorigenic characteristics, focusing particularly on the early stages of malignancy development. Recently, we generated biallelically and monoallelically PALB2-mutated cell lines in a non-malignant background and reported that also their migratory capacity had enhanced together with changes in their transcriptomes and formation of three-dimensionally grown spheroids. Here we demonstrate that JAM3 and PARVB are among the top up-regulated genes in PALB2-mutated cells and that knockdown of the genes reduce migration of the cells and morphological abnormalities of PALB2-mutated spheroids. Macropinocytosis that cancer cells utilize to advance their viability, has also enhanced in PALB2-mutated cells in a β-parvin-dependent manner. Knocking down PALB2 or increased DNA damage did not trigger JAM3 and PARVB expression in control cells, suggesting the need for long-term changes in cell fate and/or cellular conditions. However, DNA damage boosted the nuclear accumulation of a macropinosome marker dextran, indicating that PALB2-mutated cells may use the system to replenish nucleotide stocks for DNA repair. Altogether, several mechanisms can increase the oncogenic potential of PALB2-mutated cells and may offer new approaches to treat PALB2-associated cancers.