GPER1Unravelling the effects of selective estrogen receptor modulators on colorectal cancer: a prognostic role for insulin-like growth factor binding protein-5

Obesity contributes to colorectal cancer (CRC) by elevating levels of estrogen, 27-hydroxycholesterol(27-OHC), and insulin-like growth factors (IGFs). Paradoxically, epidemiological studies show that hormone replacement therapy reduces CRC incidence and mortality, particularly in postmenopausal women, suggesting a protective role for estrogen. Estrogen and 27-OHC signal via ERα, ERβ, and GPER1, with ERβ being the predominant estrogen receptor in the colon. We observed a strong positive correlation between ERβ and IGFBP-5 in CRC tissues, and high IGFBP-5 expression was significantly associated with poor patient outcomes. Functional assays revealed that ERβ knockdown inhibited colon cancer cell proliferation and migration, accompanied by a marked reduction in IGFBP-5 expression. Co-immunoprecipitation confirmed a direct interaction between ERβ and IGFBP-5. Both estrogen and 27-OHC suppressed CRC cell proliferation and IGFBP-5 expression, but this was independent of ERβ. Combined ERβ silencing and estrogen or 27-OHC treatment enhanced DNA damage and apoptosis. Transcriptome analysis identified GPER1 as a downstream estrogen-responsive gene. Subsequent in vitro validation confirmed that GPER1 activation mediates the tumour-suppressive effects of estrogen and 27-OHC. Collectively, our findings highlight IGFBP-5 as a potential prognostic marker, demonstrate the tumour-inhibitory effect of ERβ silencing, and identify GPER1 as a promising therapeutic target linking estrogen signalling, lipid metabolism, and CRC progression.