Abstract P4-08-22: Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer

Abstract Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs in breast cancer Wenxiao Ji1, Emily Ling Xin1,2, Lin Ye1, Eleri Davies3, Wen G. Jiang1, Tracey A. Martin1 1CCMRC, Cardiff University School of Medicine, Cardiff, Wales, UK 2Breast Centre, Peking University First Hospital, Xicheng District, Beijing, China 3Wales Breast Centre, University Llandough Hospital, Cardiff CF64 2XX, UK Introduction. DUSP7 is a member of the large Dual specific phosphatase family, able to regulate the phosphorylation of both tyrosine and serine/threonine protein kinases. The role of DUSP7 in cancer is not clear, however, it has been identified as a possible target for therapy in cancers including breast cancer. It has also been reported as having value in prognosis of certain cancers, such as haematological malignancies, breast cancer and certain types of gynaecological cancer. The signalling network for DUSP7 is not fully established but is known to connect to ERKs and MAP2Ks. DUSP7 also appears to be linked with salt inducible kinases (SIKs), a small family of kinases linked with progression and response to therapies in breast cancer. Thus, DUSP7 and salt inducible kinases may interact with each other and with the downstream kinases including MAP2Ks and STK11 to influence the clinical course of breast cancer. The present study explored if the pattern of DUSP7 together with salt inducible kinases and the downstream MKKs in breast cancer. Methods. The expression of DUSP7 was quantified in a cohort of breast cancer tissues (both normal mammary tissues and breast cancer tissues). The expression of the potential downstream kinases including MKK1, MKK2, MKK3, MKK4 and STK11 was also quantified. The expression profile of these molecule, together with the salt inducible kinases reported to be aberrant in our previous studies, were analysed against clinical and outcome information. Results. Breast cancer tissues expressed high levels of DUSP7 compared with normal mammary tissues, although not statistically significant. When we explored the relationship between DUSP7 and other potential related molecules in the database of the cohort, we found a highly significant correlation between DUSP7 and SIK1 (r=0.385, p< 0.001), SIK2 (r=0.590, p< 0.001), but not SIK3 (r=0.158, p>0.05). Together with SIK1 and SIK2 (known to link to drug sensitivity), DUSP7, MKK1 (MAP2K1) and MKK3 (MAP2K3) appear to form a gene signature that is of significant value in predicting the overall survival of the patients (ROC 0.723, p=0.001). This allowed us to significantly distinguish between those with good OS and poor OS (p< 0.001, Hazard Ration (HR) =1.443 (95%CI 1.154-1.804)). Multivariate analysis has shown that this signature is independent in predicting overall survival (p=0.013, HR=1.432). The signature is more significant in predicting OS in ER(-) tumours (p< 0.001) than ER(+) tumours (p=0.61). The same is seen when predicting OS with triple negative breast cancers (TNBC) (p< 0.001) than non-TNBC tumours (p=0.044). The gene signature also predicted disease free outcome (p=0.007, HR=1.266 (95% CI 1.065-1.504)). Conclusion. The dual specific phosphatase DUSP7 together with potentially correlated salt inducible kinases (SIK-1 and SIK-2) and downstream MKKs (MKK-1 and MKK3) have important clinical value in breast cancer. This provides support that DUSP7 may be a valuable therapeutic target in breast cancer. Citation Format: WENXIAO JI, Ling Xin, Eleri Davies, Wen G. Jiang, Lin Ye. Expression of Dual Specific Phosphatase-7 (DUSP7/PYST2) and it’s Connection with Salt Inducible Kinases (SIKs) and Downstream MKKs 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 P4-08-22.