Abstract P3-01-20: Werner syndrome protein (WRN) is a negative regulator of cellular migration of breast cancer cells and is associated with the clinical outcome in breast cancer

Abstract

Abstract Background: Defective human Werner Syndrome protein (WRN), encoded by a single gene is evident in patients with Werner Syndrome (WS) which is an autosomal recessive disorder with appearance of premature aging. Adults with Werner Syndrome present increased incidence of neoplasia, such as thyroid cancers, malignant melanoma, soft tissue sarcomas and some other solid tumours. The present study explored the expression of WRN in breast cancer tissues, its connection with the progression and the survival of breast cancer patients. Impact of WRN on breast cancer cells was also determined. Method: Breast tumours (n=103) together with adjacent background tissues were collected immediately after the surgery and stored at -80°C until use. Total RNA was isolated from the frozen tissues followed by reverse transcription. WRN transcript was determined by Real-Time PCR. Relevance of WRN transcript levels and pathology/clinical features was analysed using SPSS. Knockdown of WRN was carried out with anti-WRN transgenes in human breast cancer cell lines. The In vitro biological effects of altered WRN expression was evaluated by a series of in vitro cellular functional assays. Results: WRN levels in breast tumours were found to be progressively decreased from early to late stage tumours. WRN expression was markedly reduced in tumours from patients who died from breast cancer or with local recurrence, in comparison with those patients who remained disease free. The Kaplan-Meier survival model was used to analyse the overall survival and disease-free survival status of patients. It was found that patients with higher WRN transcript levels had a longer overall survival (95 % CI = 129.6-153.9 months), versus that of patients with lower transcript levels (95 % CI = 112.5-134.9 months). The patients with higher WRN expression tumours also had longer disease-free survival (95 % CI = 119.7-149.1 months) versus that of patients with lower WRN expression tumours (95 % CI = 108.0-131.3 months). Knockdown of WRN in human MDA-MB-231 breast cancer cells markedly increased their migration. Similar effect was also seen in the cells when they were exposed to a small WRN inhibitory compound. WRN were found to be significantly correlated with a group of PUFA metabolising enzymes including α6D (delta-6-desaturate) and 15-LOXB (15-lipooxygenase), indicating that it may be involved in lipid regulated cell motility. Conclusion: There is a correlation between WRN and breast cancer progression and an association between WRN and the survival of patients with breast cancer. Breast cancer cells presented an increase of cell migration following the knockdown of WRN. Collectively, WRN is a putative suppressor of aggressive traits of breast cancer cells which warrants further investigation. Citation Format: Shuo Cai, Lin Ye, Zhe Zhao, Jane Lane, Tracey A. Martin, Eleri Davies, Robert E. Mansel, Wen G. Jiang. Werner syndrome protein (WRN) is a negative regulator of cellular migration of breast cancer cells and is associated with the clinical outcome in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-01-20.