PO-300 CIP2A-mediated regulation of senescence in basal-like breast cancer

Introduction Basal-like breast cancer (BLBC) is an aggressive breast cancer molecular subtype, and it lacks efficient therapy options. Expression levels of oncoprotein CIP2A are increased in BLBC as compared to other breast cancer subtypes. Our results demonstrate that high CIP2A expression significantly predicts poor patient survival in triple negative breast cancer, that constitutes a major subset of BLBC. CIP2A inhibition also significantly impairs tumour growth of human BLBC xenografts. Previously, we have shown that CIP2A promotes breast cancer by inhibiting senescent growth arrest (Laine et al. Cancer Discov 2013). Induction of senescence and senescence associated secretome (SASP) has been shown to alter function of tumour infiltrating immune cells. Based on this we hypothesise that in addition to effects of CIP2A-mediated senescence inhibition to tumour cell-intrinsic mechanisms, it may impact infiltrating immune cells and thus therapy response. Material and methods To investigate the role of CIP2A in BLBC a carcinogen DMBA-induced tumour formation approach in Cip2a-/- mouse model was applied. In order to test our hypothesis about the effect of CIP2A-targeted senescence in immune cells we have set up mouse mammary tumour cell and organoid cultures from a spontaneous BLBC genetically engineered mouse model K14Cre;Brca1 fl/fl ;Tp53 fl/fl . These cultures are genetically manipulated by CRISPR/Cas9 system to knock out CIP2A both prior to transplantation into recipient mice and in established tumours. To validate the in vivo findings we are using several different human breast cancer patient cohorts. Results and discussions Our results demonstrate that CIP2A-deficient mice are severely impaired in a formation of DMBA-induced basal-like mammary tumours. Together with the clinical data, these results suggest that CIP2A is a novel driver oncoprotein, and a potential therapeutic target, in human BLBC. In addition, we have validated the tumour cell-intrinsic role of CIP2A in K14Cre;Brca1 fl/fl ;Tp53 fl/fl BLBC mouse model as loss of CIP2A induces senescent growth arrest in mammary gland tumour cells in vitro . Currently, we are studying the interplay between the immune system and CIP2A-inhibited tumours in vitro and in vivo . Conclusion Overall, this study will address feasibility of CIP2A targeting as a novel approach to combat basal-like breast cancer. Results of this project will also enhance our general understanding of cross-talk between senescent cancer cells and the tumour environment in this clinically challenging human cancer type.