2. Academic Validation
  3. G protein subtype preference dictates paroxetine-enhanced serotonin receptor response in non-malignant breast epithelial cells

G protein subtype preference dictates paroxetine-enhanced serotonin receptor response in non-malignant breast epithelial cells

  • Biochem Pharmacol. 2026 Feb:244:117584. doi: 10.1016/j.bcp.2025.117584.
Máté Lengyel 1,  Péter Árkosy 2,  Iván P Uray 3
Affiliations

Affiliations

  • 1 Department of of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; The Molecular, Cell and Immune Biology Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Department Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 2 Department Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
  • 3 Department of of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; The Molecular, Cell and Immune Biology Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen, Hungary; Department Clinical Oncology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary. Electronic address: [email protected].
PMID: 41344514 DOI: 10.1016/j.bcp.2025.117584
Abstract

Serotonin (5-HT) plays a key role in shaping mammary tissue morphology and regulating growth, lactation and involution. Serotonin re-uptake inhibitors (SSRIs) retain 5-HT outside the cell membrane, but their impact on breast Cancer risk through altered cell proliferation is unclear. Using transcriptomic and signaling profiles and a systematic screen of receptor-selective ligands we assessed the impact of 5-HT Receptor activation on non-malignant breast cell growth. Paroxetine reduced 5-HT levels in immortalized primary breast epithelial (HME-hTert) cells, mitigated free oxygen radical formation and decreased cell migration and proliferation. Thus, pathways related to cell cycle and DNA damage repair were underrepresented in the transcriptomic profile of paroxetine-treated cells. However, enriched transcipts overrepresented genes affecting neural transmission and GPCR signaling, suggesting an increase in 5-HT Receptor activation. As 5-HT induced the levels of both cAMP and inositol triphosphate (IP3), the contributions of individual receptors were deciphered using receptor-selective agonists and antagonists. 5-HT receptors coupled to every Gα protein subtype were expressed and functional. The activation of the GS-coupled receptor 5-HT7 and the antagonists of Gi- and Gq-coupled 5-HT1D and 5-HT2B receptors generally suppressed proliferation. Paroxetine-dependent growth suppression was reversed by inhibitors of GS-coupled 5-HT7 receptor, protein kinase A, adenylyl cyclase, and agonists of Gi and Gq-coupled receptors. This matrix of interactions suggest that the anti-proliferative responses to 5-HT in non-malignant breast cells align with the G protein preference of the receptors. The potential benefits of repurposing receptor subtype-selective agents and SSRIs, and their ideal combinations, represent a novel opportunity for Cancer risk reduction.

Keywords

5-HT receptor; Breast cancer prevention; Growth suppression; Paroxetine; Serotonin.

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