Abstract P2-11-33: Striatin and its interactive proteins Protein Phosphatase-2 (PP2) and PP2 regulatory elements in breast cancer

Abstract Introduction. The striatin protein family are calmodulin binding scaffolding proteins. Striatins have been involved in cell signalling and recently found also acting as cell adhesion molecules and adhesion regulators in adherens junctions and tight junctions. Straitins, particularly striatin-2 forms a recently discovered protein complex, STRIPAK, with other complex members including Protein Phosphatase-2 (PP2), STRIP, SIKE1 and certain PP2 regulatory proteins. The STRIPAK regulates multiple cell functions including gene transcription, endo- and exocytosis and cell adhesion, and several other important cell functions in cancer development and progression. The constitute members of the striatin protein complex may thus have important clinical bearings. In the present study, we investigated the expression profile of the striatin family members and key members of their interacting proteins, and discerned the relationship between the expression and disease progression and clinical outcome. Methods. Using an established fresh frozen breast cancer tissues cohort that included both normal mammary tissues and cancer tissues, we quantitatively evaluated the transcript expression of striatin-1 (STRN), striatin-3 (STRN3), straitin-4 (STRN4), its key regulator calmodulin (CALM) and the protein complex regulators protein phosphatase-2A (PPP2A), -2B (PPP2B) and the PPP2 regulatory elements PPP2R4 and PPP2R1A. The expression of each molecule was assessed against the clinical, pathological and prognostic factors of the patients. The integrated pattern of the complex members were also tested against the clinical outcome. Results. All three striatin members were expressed at good levels in mammary tissues and cancer tissues. STRN had little significant value against clinical and pathological factors. STRN3 and STRN4 were seen at high levels in tumours of high grade, with node positivity and with breast cancer related incidence. It was high level expressions of STRN3, STRN4 and CALM that were respectively associated with shorter overall survival (OS) of the patients and together they formed a poor prognostic indicator (p=0.034, HR=1.7). STRN had little impact on clinical outcomes. In a clear contrast, high levels of PPP2A, PPP2B and PPPR1A, but not PPP2R4, were seen in patients with significantly longer OS and together form a favourable prognostic indicator (p=0.034, HR=0.685). Integration of both STRN group and PPP2 group indicators constitutes a highly significant prognostic indicator for OS (p< 0.00001, HR=2.1 (95%CI 1.36-3.07)) and DFS (p=0.003, HR=1.402 (95%CI 1.12-1.75)). The predictive value of the integrated profile is independent of other clinical, pathological and hormone receptor status in multivariate analyses with OS (p< 0.0001, HR=3.861) and for DFS (p< 0.001, HR=2.055 (95%CI 1.36-3.07)). The same value stands when applied for the subtypes including triple negative breast cancers. Discussion. The STRIPAK complexes including Striatins play important regulatory roles in various cell functions and cancer development. Consistently, we found that high level expressions of STRN3, STRN4 and CALM, as a poor prognostic indicator were associated with shorter overall survival (OS) of the patients, while high levels of PPP2A, PPP2B and PPPR1A, as a favourable prognostic indicator, were seen in patients with significantly longer OS. Combination of both STRN group and PPP2 group indicators constitutes a greater significant prognostic indicator for OS and DFS. Future studies should focus on investigating the exact roles of the STRIPAK in cancer development and progression. Citation Format: Amber Xinyu Li, Andrew J. Sanders, Tracey A. Martin, Lin Ye, Fiona Ruge, QingPing Dou, Eleri Davies, Wen G. Jiang. Striatin and its interactive proteins Protein Phosphatase-2 (PP2) and PP2 regulatory elements in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-33.