PRJNA505181
Spontaneous ovarian tumors in TgMISIIR-TAg-DR26 BECN1+/- and BECN+/+ animals
Autophagy has been described as both a tumor suppressor pathway and an oncogenic pathway. Its function likely depends on context. In particular, BECN1 and autophagy have been highlighted as tumor promoting in Ras-driven cancers, but potentially tumor suppressing in breast and ovarian cancers. However, the role of BECN1 is complicated due to its genomic proximity to BRCA1 on both murine (chromosome 11) and human (chromosome 17) genomes. Often, both are monoallelically co-deleted in human breast and ovarian cancers. To investigate possible tumor suppressor roles of beclin and autophagy specifically in ovarian cancer, BECN1 and the core autophagy gene MAP1LC3B were knocked-down in a human atypical (BECN1+/+ and MAP1LC3B+/+) ovarian cancer cell line, SKOV3. We further investigated the causal role of BECN1 haploinsufficiency in a MISIIR SV40 large T antigen driven spontaneous ovarian cancer mouse model. Reduced autophagy gene dosage yielded genome-wide aneuploidy; both multi-megabase changes and focal copy number alterations (CNAs) were increased. Earlier tumors were observed by ultrasound in BECN1+/- mice, although lethality of tumors was not statistically different from BECN1+/+ littermate controls. An increase in copy number alterations per chromosome was observed in BECN1+/- murine tumors. Monoallelic BECN1 loss is causal for tumor initiation and genomic instability in ovarian cancer.