title: Estrogen upregulates the IGF-1 signaling pathway in lung cancer through estrogen receptor-β.
abstract: The estrogen receptor (ER) signaling and the insulin-like growth factor-1 receptor (IGF-1R) signaling are implicated in lung cancer progression. Here, we sought to investigate whether estrogen regulated the IGF-1R signaling in non-small cell lung cancer (NSCLC) and the underlying mechanisms. We examined and analyzed the correlation of the expression of aromatase (Arom), ERβ, ERα, insulin-like growth factor-1 (IGF-1), and IGF-1R in NSCLC. Tissue-microarray and immunohistochemistry analysis of tissue specimens from 162 NSCLC patients and 38 patients with benign pulmonary lesions showed that Arom, ERβ, IGF-1, and IGF-1R were overexpressed while ERα was not expressed in NSCLC. Furthermore, ERβ expression was positively correlated with that of Arom, IGF-1, and IGF-1R (r=0.554, 0.649, 0.496, respectively, P values are equal to 0.000), while Arom expression was positively associated with that of IGF-1 and IGF-1R (r=0.657, 0.714, respectively, P values are equal to 0.000). Additionally, ERβ, IGF-1, and phospho-IGF-1R, but not ERα, were expressed in A549 cells. Immunoblotting assays showed that A549 cells treated with E2 showed significantly higher IGF-1 and p-IGF-1R levels than those receiving the combination treatment of 17β-estradiol (E2) and fulvestrant (Ful, ER antagonist) (P=0.042, 0.002, respectively) or controls (P values are equal to 0.000). The MTT assays further revealed that E2 and IGF-1 synergistically promoted A549 cell proliferation. Together, our study provides the first direct evidence for an interaction between ER and IGF-1R in lung cancer. We showed that estrogen upregulated the IGF-1R signaling through ERβ in lung cancer tissues and A549 cells. These findings shed further light on the mechanisms whereby estrogen promotes lung cancer and highlight the ER and IGF-1R signaling pathways as promising targets for combinational therapy for lung cancer.
authors.affiliation: Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Dadao Street 1095, Wuhan, 430030, Hubei province, China.
authors.forename: Hexiao
authors.initials: H
authors.lastname: Tang
authors.forename: Yongde
authors.initials: Y
authors.lastname: Liao
authors.forename: Guang
authors.initials: G
authors.lastname: Chen
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xu
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Ju
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
mesh_terms: D000368:Aged; D001141:Aromatase / Q000032:analysis; D045744:Cell Line, Tumor; D004958:Estradiol / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000032:analysis / Q000502:physiology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000502:physiology*; D008175:Lung Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017526:Receptor, IGF Type 1 / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D046888:Tissue Array Analysis
chemical_list: D047629:Estrogen Receptor beta; D004958:Estradiol; D007334:Insulin-Like Growth Factor I; D001141:Aromatase; D017526:Receptor, IGF Type 1