Variation in the protein phosphatase 2A (PP2A) complex is a common event in breast cancer patients

Abstract

Objective: Triple negative breast cancer (TNBC) patients derive little benefit from target-specific therapies due to lack of the favourable prognostic targets, ER/PR and HER2. Deregulation of the PP2A complex in breast cancer will be investigated.

Methods: RNASeqV2 and clinical data were obtained from The Cancer Genome Atlas to investigate the PP2A enzyme complex across different breast cancer subtypes. Immunohistochemistry was used to measure expression in FFPE material. An Affymetrix/Panomics panel was used to assay molecular classifiers and transcripts of interest.

Results: In silico analysis of datasets (cBioPortal) show that 59.6% of basal breast tumours patients exhibit either homozygous deletion or underexpression of PP2A, but also overexpression of PP2A regulators CIP2A, SET and SETBP1. CIP2A is significantly upregulated in the HER2 positive patients and the TNBC subgroup (p<0.001). Of interest, although SET was significantly upregulated, the SETBP1 expression was also downregulated, hence stability of SET is compromised across all subtypes.

Conclusion: TNBC tumours show the greatest overexpression of CIP2A associating CIP2A with the TNBC malignant phenotype. Currently, immunohistochemistry is used to measure CIP2A expression in FFPE tissues and the correlation with expression of molecular classifiers and clinical datasets is assessed. The subset of patients with suppressed PP2A activity would be eligible for treatment using phosphatase activators or kinase inhibitors which target the PI3K/Akt/mTOR pathway.