Abstract 347: The role of Pin1 in chemosensitivity of BRCA1-deficient breast cancers

Abstract

Abstract BRCA1-deficient breast cancers are largely triple negative (ERα, PR and HER2 negative) and express markers representing the basal-like subgroup. Triple receptor negativity means that there are no targeted therapies available for this subtype, which consequently has the poorest overall survival rates. Given that BRCA1 dysfunction or ‘BRCAness’ is often observed in triple negative breast cancers (TNBCs), it is likely that loss of BRCA1 also plays a key role in their pathogenesis. Therefore to improve TNBC treatment responses, investigation into the underlying biology is required. It has been reported that levels of the prolyl isomerase Pin1 are upregulated in the absence of functional BRCA1, and that levels correlate with tumor grade. Pin1 alters the conformation of target proteins to affect their regulation and function. Many of these target proteins are implicated in key oncogenic signalling pathways, including BRCA1-associated pathways, such as cell cycle and growth regulation, DNA damage response, transcriptional regulation and NFκB signalling. We have observed that Pin1 levels are indeed upregulated in BRCA1-deficent cell lines compared to matched BRCA1 reconstituted cells, and that Pin1 plays a role in their growth rate and responsiveness to chemotherapy. BRCA1-deficient cells are sensitive to DNA damaging agents due to loss of DNA repair functions, notably homologous recombination (HR) repair of double strand breaks. We have identified a correlation between Pin1 levels and sensitivity to PARP inhibitors, which are toxic to HR deficient cells due to synthetic lethality. Ongoing work will establish whether Pin1 levels may be utilized as a biomarker of BRCAness and PARP inhibitor sensitivity. In contrast, during treatment of breast cancer cells with microtubule damaging agents, the presence of BRCA1 is required to promote apoptosis through MEKK3 and JNK, therefore BRCA1 deficient cells are less sensitive. Knockdown of Pin1 in BRCA1-deficient cells sensitizes them to the taxane Paclitaxel, due to repression of the anti-apoptotic protein Mcl-1, while Pin1 knockdown in BRCA1 proficient cells has no effect on sensitivity as Mcl-1 levels are repressed through the MEKK3 pathway. We have also identified that several Src family kinases (SFKs) are upregulated by Pin1 in a BRCA1-deficient background, and may play a role in taxane sensitivity. Pre-treatment with the Src/SFK inhibitor Dasatinib increases cytotoxicity of Paclitaxel, suggesting that combination treatment of Dasatinib and Paclitaxel may be an effective treatment option for BRCA1-deficient breast cancers. In conclusion, we have found that Pin1 may be an important oncogenic mediator downstream of dysfunctional BRCA1 facilitating the viability of TNBCs. We propose that Pin1 could serve as a predictive marker of PARP and Src inhibitor treatments, allowing clinicians to make better informed treatment decisions for this heterogeneous and aggressive subtype of breast cancer. Citation Format: Catherine Knowlson, Paul Mullan, Niamh Buckley. The role of Pin1 in chemosensitivity of BRCA1-deficient breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 347. doi:10.1158/1538-7445.AM2017-347