Estrogen And Insulin-like Growth Factor1Synergistically Promote The Development Of Lung Adenocarcinoma In Mice

Objective: Estrogen receptor (ER) and insulin-like growth factor-1receptor(IGF-1R) signaling are implicated in lung cancer progression. Based on our previousfindings, we sought to investigate whether estrogen and IGF-1act synergistically topromote lung adenocarcinoma (LADE) development in mice.Methods: LADE was induced with urethane in ovariectomized Kunming mice.Tumor-bearing mice were divided into seven groups:17β-estradiol (E2),E2+fulvestrant (Ful; estrogen inhibitor), IGF-1, IGF-1+AG1024(IGF-1inhibitor),E2+IGF-1, E2+IGF-1+Ful+AG1024, and control groups. After14weeks, the micewere sacrificed and tumor growth was determined. The expression of ERα/ERβ,IGF-1, IGF-1R, and Ki67was examined usingtissue-microarray-immunohistochemistry, and IGF-1, p-ERβ, p-IGF-1R, p-MAPK,and p-AKT levels were determined based on Western blot analysis.Fluorescence-quantitative PCR was used to detect the mRNAexpression of ERβ,ERβ2, and IGF-1R.Results: Tumors were found in93.88%(46/49) of urethane-treated mice, andpathologically proven LADE was noted in75.51%(37/49). In the E2+IGF-1group,tumor growth was significantly higher than in the E2group (P <0.05), the IGF-1group (P <0.05), and control group (P <0.05). Similarly, the expression of ERβ, p-ERβ,ERβ2, IGF-1, IGF-1R, p-IGF-1R, p-MAPK, p-AKT, and Ki67at the protein and/ormRNA levels were markedly higher in the ligand group than in the ligand+inhibitor groups (all P <0.05).Conclusion: The present study demonstrated for the first time that estrogen andIGF-1act to synergistically promote the development of LADE in mice, and this maybe related to the activation of the MAPK and AKT signaling pathways in which ERβ1,ERβ2, and IGF-1R play important roles.