HTR1A Inhibits the Progression of Triple-Negative Breast Cancer via TGF-β Canonical and Noncanonical Pathways

Triple-negative breast cancer is the most aggressive subtype of breast cancer and the incidence of depression in breast cancer patients is high, which leading to worse survival and increased risk of recurrence. The effect of antidepressants on breast cancer patients remains contradictory, which might be due to variations in antidepression targets. Therefore, there is significant value to explore the antitumor potential of antidepressants and discover new therapeutic targets for breast patients. The authors screen antidepressant-related oncogenes or suppressors by using siRNAs. After combining functional experiments with online database analysis, 5-hydroxytryptamine receptor 1A (HTR1A is selected with antitumor potential in breast cancer cells in vivo and in vitro. RNA-seq analysis and coimmunoprecipitation assays indicate that HTR1A interacts with TRIM21 and PSMD7 to inhibit the degradation of TβRII through the ubiquitin-proteasome pathway, thereby inhibiting the transforming growth factor-β (TGF-β) canonical and noncanonical pathway. In addition, HTR1A is an independent predictive factor for breast cancer patients. The combined treatment of HTR1A agonists with demethylation drugs may significantly improve patient survival. It is of great significance to clarify the function and mechanism of the depression-related gene HTR1A in breast cancer, which might provide a new approach for triple-negative breast cancer patients.