Abstract 1993P
Background
HER2 positive tumors are known as an aggressive disease. The phenotype is characterized by amplification at 17q12-q21. ERBB2 amplification along with HER2 protein expression was described in extravillous trophoblast (EVT) cells during first trimester pregnancy. HER2 signaling pathway activation is a physiologic process controlling EVT cell invasion and vascular organization. Identifying the dysfunctional modulation on ERBB2 amplicon in cancer is a key point to develop more effective therapies for HER2-enriched cancer patients.
Methods
Publicly available databases were used to inferred copy number variation (RRBS with MethGo tool) and to analyze the transcriptome from trophoblast cells (DESeq2). RNAseq and SNP array from breast, stomach and esophagus carcinomas from TCGA were used for integrative and comparative in silico analyses in order to identify dysfunctional regulation on cancer HER2-signilaing pathway.
Results
Virtually all ERBB2 amplified cancer samples exhibit a core amplification affecting STARD3, TCAP, PNMT, PGAP3, ERBB2 and GRB7 genes (r > 0.99). An additional 17 genes have a high copy number correlation (r > 0. 75) with ERBB2. Five of them have high correlation with ERBB2 expression (PGAP3, STARD3, GRB7, ORMDL3, PSMD3 and PNMT) suggesting they may cooperate to ERBB2 signaling. In trophoblastic cells, there is an amplification region at the long arm of chr17 affecting 58 genes including the ERBB2. Although all those genes are amplified in all trophoblast cells, the genes GRB7, PGAP3, STARD3 and PSMD3 are down regulated in EVT, suggesting the presence of regulatory mechanisms modulating the amplicon expression. Protein integration analysis identified a network connecting ERBB2, GRB7 and PSMD3 in association to STARD3 and PGAP3. GRB7 is known to interact with EGFRs and plays a role in the integrin signaling pathway and cell migration. PSMD3 has a post-translational role in stabilizing HER2, avoiding its degradation.
Conclusions
This integrative and comparative in silico analysis of physiologic/pathologic process is the first report suggesting the dysfunction on ERBB2, GRB7, PGAP3, STARD3 and PSMD3 network may be crucial for the lethal HER2-pathway in cancer.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Daniel G Tiezzi.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.