Basal-like breast cancer (BLBC) is an aggressive and therapeutically most challenging breast cancer subtype, due to a lack of druggable breast specific surface receptors (ER, PR, HER2) or driver mechanisms. BLBC patients are treated mainly with standard chemotherapies but due to poor patient stratification strategies, a vast majority of patients receive aggressive chemotherapy even though some of them could be spared from its unnecessary side effects. Protein Phosphatase 2A (PP2A) is an important serine-threonine tumor suppressor phosphatase and its inactivation is an important requirement for malignant transformation in humans. In this dissertation, we demonstrate the role of PP2A inhibitor protein CIP2A (Cancerous Inhibitor of PP2A) in BLBC.

We identified a novel PP2A-independent role for CIP2A as a non-genetic driver protein and a biomarker of poor prognosis in BLBC. We discovered that CIP2A interacts with DNA damage response protein TopBP1, prevents its recruitment at the site of DNA damage and allows the progression of damaged cells into mitosis. We further established that CIP2A drives BLBC by coordinating the BLBC hallmarks. CIP2A controls the high proliferation activity of MYC and E2F1 by preventing their dephosphorylation by PP2A but also promotes high genomic instability by deregulating the G2/M checkpoint (PP2A-independent role). We also identified that CIP2A is a synthetic lethal target in BRCA mutant BLBCs and established that CIP2A is selectively more important in predicting prognosis of basal-like TNBC patients compared to non basal-like TNBC subtype.

To develop these findings towards clinical utility, we further developed a robust CIP2A transcriptional signature and highlighted several applications of this tool for BLBC patients. The CIP2A signature can predict the aggressivity of breast cancer and it was used to identify drugs and drug combinations that show clinical benefit for the different stratified BLBC subgroups.

Collectively, this dissertation reports the yet uncharacterized role of CIP2A in DNA Damage response (DDR), BLBC tumorigenesis, and its potential use as a personalized medicine strategy for effective clinical management of BLBC.