A STAT1-GBP1 axis modulates epithelial proliferation in postpartum breast tissue by repressing CDKI expression.

BACKGROUND: Postpartum breast cancer, diagnosed within five years of childbirth, is associated with heightened mortality compared to breast cancers in nulliparous women. Although the postpartum breast undergoes extensive involution and remodeling, the molecular drivers that promote subsequent tumor development remain incompletely understood. We investigated whether signal transducer and activator of transcription 1 (STAT1) and guanylate binding protein 1 (GBP1) contribute to epithelial proliferation through suppression of cyclin-dependent kinase inhibitors (CDKIs). METHODS: Formalin-fixed, paraffin-embedded postpartum (n = 5) and nulliparous (n = 5) benign breast tissues were profiled using transcriptomic panels targeting oncogenic and immunologic pathways. Protein expression of STAT1, GBP1, and the proliferation marker Ki67 was examined by immunohistochemistry. Functional studies were performed in human mammary epithelial cells (HMECs) derived from the same postpartum and nulliparous tissues. Small interfering RNA (siRNA) and lentiviral knockdown strategies were used to reduce STAT1 and GBP1, followed by assessment of CDKI expression, cell cycle distribution, and cell proliferation. RESULTS: Transcriptomic profiling revealed a postpartumspecific interferon signature (STAT1, GBP1), elevated Ki67, and reduced CDKIs; immunofluorescence across > 200 lobules confirmed these increases and suggested that GBP1 fully mediates the STAT1-Ki67 link. In HMECs, knockdown of STAT1 or GBP1 induced a marked rise in p21 and p57 (CDKN1A and CDKN1C), accompanied by G1 cell cycle arrest and reduced proliferation. Combined knockdown had an additive effect on suppressing epithelial proliferation, suggesting a cooperative role for STAT1 and GBP1 in modulating cell cycle progression. CONCLUSIONS: These findings identify a STAT1-GBP1 axis that enhances postpartum epithelial proliferation by repressing CDKI expression. This mechanism may help to explain the heightened vulnerability observed after childbirth and highlights potential biomarkers or early intervention targets in postpartum breast tissues.