Although both kinases and phosphatases have equally important roles in maintaining cellular homeostasis, the protein phosphatases are understudied and their functional relevance in human malignancies is not fully understood yet. This project aims to better understand the role of a major serine threonine phosphatase called protein phosphatase 2A (PP2A) in cancer particularly basal-like breast cancer (BLBC). BLBC is the most challenging breast cancer subtype as it is very aggressive with no targeted therapies, and the main reason can be attributed to poor understanding of the molecular mechanisms that drive this cancer subtype. Hence, there is a critical clinical need to identify new targets and develop novel therapies for this subtype. Our research group discovered CIP2A (cancerous inhibitor of PP2A) (Cell, 2007) and its role as an oncoprotein in breast cancer and several studies have indicated that high CIP2A expression correlates with more aggressive cancer and poor prognosis in the clinic. This project aims to unravel the molecular mechanisms by which CIP2A drives tumour initiation in BLBC and to establish CIP2A biomarker signature which can serve as a predictive and prognostic tool for better clinical management of BLBC.
The key methods used in the project are CIP2A Knockout mouse models, RNA sequencing of basal like breast cancer cell lines, Immunohistochemistry (IHC) of patient material, DNA Damage Ionization radiation induced foci (IRIF) formation, Colony formation experiments with depletion of CIP2A using siRNA, Flow cytometry, Western blotting, Co-Immunoprecipitation (CO-IP), Immunofluorescence and microscopy.
Our results have shown that CIP2A knockout mice were resistant to DMBA induced BLBC tumour formation. Mechanistic studies indicated that it has an important role in DNA Damage Response signaling. Analysis of patient material revealed that CIP2A has a prognostic benefit particularly in basal type TNBC patients. We generated a CIP2A Biomarker signature (269 genes, p = 0.01) by RNA Seq of CIP2A depleted BLBC cell lines and validated it with publicly available TCGA and METABRIC datasets.
CIP2A is a promising novel target for BLBC and it has the potential to be used as a predictive and prognostic biomarker for BLBC.
Jukka Westermarck (Principal investigator).
Finnish Cancer Foundation, Business Finland, University of Turku Graduate School.
All authors have declared no conflicts of interest.