FAM83A conferred EMT and facilitated multidrug resistance and metastasis in breast cancer via TGF-β/Smad signaling

Objectives: 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.