Fulvestrant-Mediated Inhibition of Estrogen Receptor Signaling Slows Lung Cancer Progression

Abstract

Estrogens are key signaling molecules that regulate various physiological processes such as cell growth, development, and differentiation. They also play a major role in many pathological conditions, such as hormone-dependent cancer. The importance of inhibiting estrogen receptor signaling in diseases of estrogen target tissues, such as breast cancer, is well documented. However, the role of estrogen signaling in diseases of nontarget tissues, such as lung cancer, is not well characterized. The aim of the current study is to examine the expression of estrogen receptor (ER) and the roles of estradiol (E2) and fulvestrant on the progression of lung cancer. Tissue microarray (TMA) and immunohistochemistry (IHC) analyses were used to detect the expression of aromatase, ER, and ER in 198 patients. We performed analyses to determine if there was any correlation among these three proteins. A mouse model of urethane-induced lung adenocarcinoma was used in the study. Mice were divided into three treatment groups: blank control, E2 alone, and E2 + fulvestrant (ER antagonist). Western blot analysis and fluorescence quantitative PCR (FQ-PCR) were used to measure expression of ER protein and mRNA levels, respectively. ER, but not ER, was overexpressed in NSCLC samples. Lung cancer progression in mice treated with E2 was significantly increased compared to either the control group or the E2 + fulvestrant group. Mice in the E2 treatment group had significantly increased expression of ER at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ER promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ER in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease.