DP103 as a critical modulator of Wnt signaling and cancer stemness: implications for precision treatment in triple negative breast cancer.
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Cai Wanpei, Pohl Sebastian Öther-Gee, Lai Xianning, Lam Hiu Yan, Low Catharine Shi-Yun, Koh Vivien, Ma Haoran, Agostino Mark, Banerjee Arindam, Bunnag Nawat, Suresh Jahnavi, Deivasigamani Amudha, Yuan Yi, Tan Tuan Zea, Rajasekaran Muthukumar, Chen Jianxiang, Swa Hannah Lee Foon, Hua San Hue, Guo Shiyuan, Teng Janet Cheng-Fei, Chin Jas Min, Choy Jocelyn Yeen Hui, Thike Aye Aye, Lee Young Bok, Kanchi Madhu Mathi, Ramesh Karthik, Mok Yu Keung, Huang Ruby Yun-Ju, Gunaratne Jayantha, Fullwood Melissa Jane, Tan Puay Hoon, Yip George W, Sethi Gautam, Blaydes Jeremy P, Yap Celestial T, Lobie Peter Edward, Kok Venetia Jing-Tong, Dharmarajan Arunasalam, Hui Kam Man, Kim Deog Joong, Cheong Jit Kong, Tolwinski Nicholas, Yong Wei Peng, Tan Patrick, Myant Kevin B, Kumar Alan Prem
Аннотация
Triple-negative breast cancer (TNBC) is a clinically aggressive subtype lacking targeted therapies, often characterized by hyperactivation of the Wnt/β-catenin signaling pathway and an enriched population of cancer stem cells (CSCs). Here, we identify the DEAD-box RNA helicase DP103 as a novel modulator of Wnt/β-catenin signaling in TNBC, acting independently of its canonical helicase function. DP103 expression correlates with increased phosphorylation of LRP6 and nuclear β-catenin accumulation, enhancing Wnt transcriptional activity. Mechanistically, DP103 physically interacts with GSK3β to facilitate post-translational modifications essential for Wnt activation. Notably, DP103 itself is a Wnt target, forming a feedforward loop that sustains oncogenic signaling. Functional studies reveal that DP103 promotes CSC-like traits in TNBC cells, including self-renewal and expression of stemness markers (Nanog, Oct4, Sox2), linking its role in Wnt activation to breast cancer stemness and metastasis. In vivo studies using Drosophila models confirmed the evolutionarily conserved role of Gemin3/DP103 in epithelial transformation, though context-dependent differences were observed. Importantly, we demonstrate that RX-5902, a Wnt pathway inhibitor currently in clinical trials, suppresses DP103 expression and Wnt/β-catenin signaling, reducing TNBC cell viability and mammosphere formation without affecting normal epithelial cells. RX-5902 efficacy was abrogated by DP103 depletion, underscoring DP103's critical role in mediating drug response. In xenograft models, RX-5902 treatment significantly reduced tumor burden and prolonged survival. Collectively, our findings establish DP103 as a key regulator of Wnt-driven oncogenesis in TNBC and highlight its dual role in promoting CSC traits and therapeutic resistance. These insights position DP103 as a potential biomarker and therapeutic target to disrupt sustained Wnt signaling in TNBC, offering new avenues for precision intervention in this challenging breast cancer subtype.