23047

PDS5B

APRIN|AS3|CG008;PDS5 cohesin associated factor B;PDS5B;PDS5 cohesin associated factor B

androgen induced inhibitor of proliferation|androgen-induced proliferation inhibitor|androgen-induced prostate proliferative shutoff-associated protein AS3|androgen-induced shutoff 3|sister chromatid cohesion protein PDS5 homolog B

13q12.3

protein-coding

Although screening for large deletions or duplications of the BRCA1 gene is becoming a routine component of the molecular diagnosis of familial breast cancer, little is known about the occurrence of such rearrangements in the BRCA2 gene. Because of the high frequency of BRCA2 mutations in breast cancer families with at least one case of male breast cancer, we selected a cohort of 39 such families, tested negative for mutations in the coding regions of BRCA1 and BRCA2, and developed an assay for BRCA2 rearrangements, based on quantitative multiplex PCR of short fluorescent fragments (QMPSF). We found three rearrangements: (1) a deletion of exons 12 and 13; (2) a duplication of exons 1 and 2; and (3) a complete deletion of BRCA2. We determined the boundaries of the deletion of exons 12 and 13, showing that it resulted from an unequal recombination between Alu sequences. We mapped the complete BRCA2 deletion, which extends over at least 298 kb and showed that it does not affect APRIN/AS3, previously characterized as a tumor suppressor gene, but it comprises several loci corresponding to proven or putative transcripts of unknown functional significance. These data suggest that screening for BRCA2 rearrangements should be done, especially in male breast cancer families tested negative for BRCA1 and BRCA2 mutations.

Cohesins appear to have critical functions beyond mitotic cohesion. Our data on a cohesin-associated Pds5-paralog, APRIN, indicate a novel cohesin role in stem cell differentiation. APRIN/Pds5B is lost in many cancers and it is a putative tumor suppressor. Its mutations in the germ line, however, generate birth defects. We reasoned that as both cancer and birth defects share disrupted stem cell differentiation, the data suggest an APRIN/Pds5B cohesin function in stem cells. We used an embryonal carcinoma stem cell model and show here that (i) APRIN expression is precisely coordinated with stem cell differentiation; (ii) this coordination involves surface-contact and endocrine pathways; and (iii) APRIN/Pds5b coordination is critical in stem/progenitor exit decisions. APRIN knockdown disrupted Oct4, Nanog and SOX2 patterns, differentiation failed and the resulting immature proliferative cells did not progress beyond proneural progenitor phase. Furthermore, the phenotype-blocked progenitor exit (Mash-1(+)); failed E-cadherin exit (E-Cadh(low+)); incomplete N-cadherin transition (N-Cadh(low+)); retained proliferative capacity (c-myc(+)); irregular stemness (SOX2(late++)) and lost response to contact and hormonal cues-shares similarities with cancer-initiating cells. The data suggest novel APRIN/Pds5B-linked cohesin roles in stem/progenitor programs and a new mechanism in tumor suppression.