Estrogen and insulin‐like growth factor 1 synergistically promote the development of lung adenocarcinoma in mice

Abstract

Estrogen receptor (ER) and insulin‐like growth factor‐1 receptor (IGF‐1R) signaling are implicated in lung cancer progression. Based on their previous findings, the authors sought to investigate whether estrogen and IGF‐1 act synergistically to promote lung adenocarcinoma (LADE) development in mice. 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‐1 inhibitor), E2+IGF‐1, E2+IGF‐1+Ful+AG1024 and control groups. After 14 weeks, the mice were sacrificed, and then the tumor growth was determined. The expression of ERα/ERβ, IGF‐1, IGF‐1R and Ki67 was examined using tissue‐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 polymerase chain reaction was used to detect the mRNA expression of ERβ, ERβ2 and IGF‐1R. Tumors were found in 93.88% (46/49) of urethane‐treated mice, and pathologically proven LADE was noted in 75.51% (37/49). In the E2+IGF‐1 group, tumor growth was significantly higher than in the E2 group (p < 0.05), the IGF‐1 group (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 Ki67 at the protein and/or mRNA levels was markedly higher in the ligand group than in the ligand + inhibitor groups (all p < 0.05). This study demonstrated for the first time that estrogen and IGF‐1 act to synergistically promote the development of LADE in mice, and this may be related to the activation of the MAPK and AKT signaling pathways in which ERβ1, ERβ2 and IGF‐1R play important roles.

The regulation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumor promotion by estradiol in female A/J mice

“…We have shown that the tumor multiplicity and the inflammatory response were more obviously by E2 treatment, indicating that E2 can strongly potentiate inflammation and tumorigenesis induced by NNK (Table 2). These results are consistent with previous studies showed that estrogen not only promotes the malignant development of breast cancer, but also acts on non-target organs, including lung cancer through various molecular mechanisms [21,22]. In addition to the solitary effect of estrogen, females exposed to other environmental chemicals such as benzo [a]pyrene that may interfere with the physiological functions of estrogen leading to increasing susceptibility of cancers [23][24][25].…”

Estrogen Receptor-β Up-Regulates IGF1R Expression and Activity to Inhibit Apoptosis and Increase Growth of Medulloblastoma

“…Similar to Med, in human lung cancers, ER␤ and IGF1R expression levels are positively correlated, and increased levels of their expression are associated with poor prognosis (64). In ER␤-positive/ER␣-negative nonsmall cell lung cancer cells E2 acts via ER␤ to increase IGF1R expression and signaling, and in a mouse model of lung adenocarcinoma E2 promotes tumor development through this mechanism (64,65). It is notable that ER␣ is typically not expressed, or expressed at very low levels, in both Med and lung cancer where the tumor promoting effects of E2 increases IGF1R expression and signaling via ER␤, thus raising the possibility that ER␣ status might be a central determinant in defining the tumor growth potential of ER␤.…”

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

“…In fact, in some studies ERβ was found to be the main receptor mediating the proliferative effects of estrogens in lung cancer cells [18]. Furthermore, ERβ appears to be involved with insulin-like growth factor-1 receptor (IGF-1R) in a synergistic promotion of lung adenocarcinoma development in murine models [19]. On the other hand, other studies indicate that ERβ may have prognostic value, since its overexpression appears to be a positive prognostic marker in stage II and III non-small cell lung cancer (NSCLC) patients [20], whereas its absence, together with the presence of ERα, was associated with a poorer prognosis in patients affected by the same type of cancer [21].…”