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Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.

Hsu LH, Liu KJ, Tsai MF, Wu CR, Feng AC, Chu NM, Kao SH - Cancer Sci. (2014)

Bottom Line: We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma.We proposed a different pathway that estrogen upregulated the expression of osteopontin and then promoted cell migration through αvβ3 integrin binding and activated MEK-ERK signaling pathway, which is a common downstream pathway with epidermal growth factor receptor (EGFR) activation.An additive effect of ER antagonists and EGFR antagonists on the inhibition of cell migration was also noted.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei, Taiwan; Department of Medicine, National Yang-Ming University Medical School, Taipei, Taiwan.

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Estrogen promoted cell migration via estrogen receptor β (ERβ) activation of the MEK/ERK signaling pathway. (a) A549 cells and PE089 were subjected to wound healing assays for 24 h in the presence of 100 nM estradiol (E2), 10 μM tamoxifen citrate (T, ER antagonist), co-treatment with E2 and tamoxifen citrate (E2 + T), or ethanol equivalent as the control. (b) The wound area of A549 or PE089 cell migration was analyzed. The lines indicate the boundary of the edges of the wound after 24 h. The bars represent mean ± standard deviation relative to the cells treated with ethanol. (c) A549 and PE089 cells were cultured in the presence of E2 and/or U0126 (U, MEK inhibitor) for 24 h. U0126 reduced E2-induced cell migration. (d) Western blotting of the ERK and phosphorylated ERK of the cells treated with E2 and/or U0126 showed estrogen-induced ERK phosphorylation was inhibited by U0126. (e) Western blotting showed that ERβ was the predominant receptor type in the lung cancer cell lines. (f) Transfection of the A549 cells with the human ERβ gene or ERβ shRNA was performed to establish an ERβ overexpression cell clone (ERβ O/E) and ERβ depletion cell clone (shRNA), respectively. (g) ERβ O/E with E2 stimulation resulted in a maximal increase in cell growth rate. (h) The migratory ability of the various indicated cells was analyzed. DPN (ERβ agonist) and E2 induced migration of ERβ O/E cell. ER inhibitor (ICI 182780, ICI), tamoxifen and ERβ knockdown with shRNA resulted in a reduction of cell migration. *P < 0.05; **P < 0.01 compared with the control; #P < 0.05; ##P < 0.01 compared with the E2 group. Cv, control vector; O/E, overexpression.
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fig02: Estrogen promoted cell migration via estrogen receptor β (ERβ) activation of the MEK/ERK signaling pathway. (a) A549 cells and PE089 were subjected to wound healing assays for 24 h in the presence of 100 nM estradiol (E2), 10 μM tamoxifen citrate (T, ER antagonist), co-treatment with E2 and tamoxifen citrate (E2 + T), or ethanol equivalent as the control. (b) The wound area of A549 or PE089 cell migration was analyzed. The lines indicate the boundary of the edges of the wound after 24 h. The bars represent mean ± standard deviation relative to the cells treated with ethanol. (c) A549 and PE089 cells were cultured in the presence of E2 and/or U0126 (U, MEK inhibitor) for 24 h. U0126 reduced E2-induced cell migration. (d) Western blotting of the ERK and phosphorylated ERK of the cells treated with E2 and/or U0126 showed estrogen-induced ERK phosphorylation was inhibited by U0126. (e) Western blotting showed that ERβ was the predominant receptor type in the lung cancer cell lines. (f) Transfection of the A549 cells with the human ERβ gene or ERβ shRNA was performed to establish an ERβ overexpression cell clone (ERβ O/E) and ERβ depletion cell clone (shRNA), respectively. (g) ERβ O/E with E2 stimulation resulted in a maximal increase in cell growth rate. (h) The migratory ability of the various indicated cells was analyzed. DPN (ERβ agonist) and E2 induced migration of ERβ O/E cell. ER inhibitor (ICI 182780, ICI), tamoxifen and ERβ knockdown with shRNA resulted in a reduction of cell migration. *P < 0.05; **P < 0.01 compared with the control; #P < 0.05; ##P < 0.01 compared with the E2 group. Cv, control vector; O/E, overexpression.

Mentions: For quantification of the wound healing, the wound area of nontreated cells for 24 h is defined as 100%. Wound healing assays of A549 or PE089 cells incubated with E2 showed a significant decrease in wound area. The PE089 cells showed a higher migratory ability than the A549 cells in the presence of E2. Tamoxifen significantly reduced the E2-induced cell migration in A549 and PE089 cells (Fig.2a,b).


Estrogen adversely affects the prognosis of patients with lung adenocarcinoma.

Hsu LH, Liu KJ, Tsai MF, Wu CR, Feng AC, Chu NM, Kao SH - Cancer Sci. (2014)

Estrogen promoted cell migration via estrogen receptor β (ERβ) activation of the MEK/ERK signaling pathway. (a) A549 cells and PE089 were subjected to wound healing assays for 24 h in the presence of 100 nM estradiol (E2), 10 μM tamoxifen citrate (T, ER antagonist), co-treatment with E2 and tamoxifen citrate (E2 + T), or ethanol equivalent as the control. (b) The wound area of A549 or PE089 cell migration was analyzed. The lines indicate the boundary of the edges of the wound after 24 h. The bars represent mean ± standard deviation relative to the cells treated with ethanol. (c) A549 and PE089 cells were cultured in the presence of E2 and/or U0126 (U, MEK inhibitor) for 24 h. U0126 reduced E2-induced cell migration. (d) Western blotting of the ERK and phosphorylated ERK of the cells treated with E2 and/or U0126 showed estrogen-induced ERK phosphorylation was inhibited by U0126. (e) Western blotting showed that ERβ was the predominant receptor type in the lung cancer cell lines. (f) Transfection of the A549 cells with the human ERβ gene or ERβ shRNA was performed to establish an ERβ overexpression cell clone (ERβ O/E) and ERβ depletion cell clone (shRNA), respectively. (g) ERβ O/E with E2 stimulation resulted in a maximal increase in cell growth rate. (h) The migratory ability of the various indicated cells was analyzed. DPN (ERβ agonist) and E2 induced migration of ERβ O/E cell. ER inhibitor (ICI 182780, ICI), tamoxifen and ERβ knockdown with shRNA resulted in a reduction of cell migration. *P < 0.05; **P < 0.01 compared with the control; #P < 0.05; ##P < 0.01 compared with the E2 group. Cv, control vector; O/E, overexpression.
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fig02: Estrogen promoted cell migration via estrogen receptor β (ERβ) activation of the MEK/ERK signaling pathway. (a) A549 cells and PE089 were subjected to wound healing assays for 24 h in the presence of 100 nM estradiol (E2), 10 μM tamoxifen citrate (T, ER antagonist), co-treatment with E2 and tamoxifen citrate (E2 + T), or ethanol equivalent as the control. (b) The wound area of A549 or PE089 cell migration was analyzed. The lines indicate the boundary of the edges of the wound after 24 h. The bars represent mean ± standard deviation relative to the cells treated with ethanol. (c) A549 and PE089 cells were cultured in the presence of E2 and/or U0126 (U, MEK inhibitor) for 24 h. U0126 reduced E2-induced cell migration. (d) Western blotting of the ERK and phosphorylated ERK of the cells treated with E2 and/or U0126 showed estrogen-induced ERK phosphorylation was inhibited by U0126. (e) Western blotting showed that ERβ was the predominant receptor type in the lung cancer cell lines. (f) Transfection of the A549 cells with the human ERβ gene or ERβ shRNA was performed to establish an ERβ overexpression cell clone (ERβ O/E) and ERβ depletion cell clone (shRNA), respectively. (g) ERβ O/E with E2 stimulation resulted in a maximal increase in cell growth rate. (h) The migratory ability of the various indicated cells was analyzed. DPN (ERβ agonist) and E2 induced migration of ERβ O/E cell. ER inhibitor (ICI 182780, ICI), tamoxifen and ERβ knockdown with shRNA resulted in a reduction of cell migration. *P < 0.05; **P < 0.01 compared with the control; #P < 0.05; ##P < 0.01 compared with the E2 group. Cv, control vector; O/E, overexpression.
Mentions: For quantification of the wound healing, the wound area of nontreated cells for 24 h is defined as 100%. Wound healing assays of A549 or PE089 cells incubated with E2 showed a significant decrease in wound area. The PE089 cells showed a higher migratory ability than the A549 cells in the presence of E2. Tamoxifen significantly reduced the E2-induced cell migration in A549 and PE089 cells (Fig.2a,b).

Bottom Line: We found that the premenopausal patients had more advanced disease and a shorter survival among the never-smoking female patients with lung adenocarcinoma.We proposed a different pathway that estrogen upregulated the expression of osteopontin and then promoted cell migration through αvβ3 integrin binding and activated MEK-ERK signaling pathway, which is a common downstream pathway with epidermal growth factor receptor (EGFR) activation.An additive effect of ER antagonists and EGFR antagonists on the inhibition of cell migration was also noted.

View Article: PubMed Central - PubMed

Affiliation: Division of Pulmonary and Critical Care Medicine, Sun Yat-Sen Cancer Center, Taipei, Taiwan; Department of Medicine, National Yang-Ming University Medical School, Taipei, Taiwan.

Show MeSH
Related in: MedlinePlus