Tamoxifen Alters TGF‐β1/Smad Signaling in Vocal Fold Injury

Abstract

ObjectivesEffective treatments for vocal fold fibrosis remain elusive. Tamoxifen (TAM) is a selective estrogen receptor modulator and was recently reported to have antifibrotic actions. We hypothesized that TAM inhibits vocal fold fibrosis via altered transforming growth factor beta 1 (TGF‐β1) signaling. Both in vitro and in vivo approaches were employed to address this hypothesis.MethodsIn vitro, vocal fold fibroblasts were treated with TAM (10−8 or 10−9 M) ± TGF‐β1 (10 ng/ml) to quantify cell proliferation. The effects of TAM on genes related to fibrosis were quantified via quantitative real‐time polymerase chain reaction. In vivo, rat vocal folds were unilaterally injured, and TAM was administered by oral gavage from pre‐injury day 5 to post‐injury day 7. The rats were randomized into two groups: 0 mg/kg/day (sham) and 50 mg/kg/day (TAM). Histological changes were examined on day 56 to assess tissue architecture.ResultsTAM (10−8 M) did not affect Smad3, Smad7, Acta2, or genes related to extracellular matrix metabolism. TAM (10−8 or 10−9 M) + TGF‐β1, however, significantly increased Smad7 and Has3 expression and decreased Col1a1 and Acta2 expression compared to TGF‐β1 alone. In vivo, TAM significantly increased lamina propria area, hyaluronic acid concentration, and reduced collagen deposition compared to sham treatment.ConclusionsTAM has antifibrotic potential via the regulation of TGF‐β1/Smad signaling in vocal fold injury. These findings provide foundational data to develop innovative therapeutic options for vocal fold fibrosis.Level of EvidenceNA Laryngoscope, 133:2248–2254, 2023