FAM83A conferred EMT and facilitated multidrug resistance and metastasis in breast cancer via TGF-β/Smad signaling
Xiaowu Hu, Jiaofeng Li, Yunxuan Liu, Qing Li, Jun Jiang, Qi Wu, Qiao Li, Yang Yang, Yujun Wang, Yuzhuo Chen, Yanping Liang, Junling Liu, Yuanyuan Di, Yi Wang, Ling Lu, Zhirong YangObjectives:
Epithelial-mesenchymal transition (EMT) is a key driver of cancer progression, and Family with sequence similarity 83, member A (FAM83A) is a putative oncogene, but its specific role and mechanism in breast cancer (BC) EMT, metastasis, and multidrug resistance remain unclear.
Materials and Methods:
FAM83A expression was analyzed using public BC transcriptomic datasets and BC cell lines. Gain- and loss-of-function approaches were used to assess its effects on drug resistance (doxorubicin and 5-fluorouracil), migration, invasion, and EMT-related molecular changes. The involvement of transforming growth factor-beta (TGF-β)/Smad signaling was tested using a specific Smad3 inhibitor.
Results:
FAM83A was upregulated in BC datasets and BC cell lines, and high FAM83A expression was associated with worse overall survival, recurrence-free survival, distant metastasis-free survival, and post-progression survival. Overexpression of FAM83A increased multidrug resistance, migration, invasion, and EMT-like changes, while silencing FAM83A had opposite effects. FAM83A activated TGF-β/Smad signaling, and inhibiting Smad3 reversed FAM83A-induced transcriptional activity, EMT changes, metastasis, and multidrug resistance.
Conclusion:
FAM83A promoted BC EMT, metastasis, and multidrug resistance through TGF-β/Smad signaling in vitro , providing a pre-clinical experimental basis for future studies on BC progression and therapeutics.