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 β (ERβ) 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, ERα, and ERβ 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 (ERβ antagonist). Western blot analysis and fluorescence quantitative PCR (FQ-PCR) were used to measure expression of ERβ protein and mRNA levels, respectively. ERβ, but not ERα, 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 ERβ at both the mRNA and protein levels compared to mice treated with E2 + fulvestrant or control. Our data suggest that ERβ promotes lung cancer progression in mice and that this progression can be inhibited with fulvestrant. These findings may help elucidate the role of ERβ in lung cancer and suggest that estrogen receptor antagonists, such as fulvestrant, may be therapeutically beneficial for the treatment of the disease.

A Single-Center Retrospective Study of Patients with Double Primary Cancers: Breast Cancer and <b><i>EGFR</i></b>-Mutant Non-Small Cell Lung Cancer

“…Interaction between the ER and EGFR has been described, and a preclinical trial suggested that the development of both BC and LC may be related to the ER pathway. Recent studies have demonstrated that NSCLCs express ER and that fulvestrant, an antiestrogen that reduces the ER protein, inhibits the proliferation of LC cells [31]. Combination treatment with an EGFR-TKI and fulvestrant showed greater efficacy than the TKI or fulvestrant alone in vitro and in vivo [32].…”

Interaction of estrogen receptor β5 and interleukin 6 receptor in the progression of non–small cell lung cancer

“…In the tissues of normal lung and non‐small cell lung cancer (NSCLC), ERβ has a higher expression compared with ERα . A number of studies, including ours, have shown that E2 can promote the development and progression of lung cancer through ERβ …”

CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

“…In addition, the LXXLL motif of CLPTM1L and mass spectrographic analysis of CLPTM1L in A549 cells suggested that the nuclear receptor ERβ interacted with CLPTM1L in the cells. ERα and ERβ affect the survival of lung cancer patients by promoting the proliferation of cancer cells [85,86], and ERβ is expressed at higher levels than ERα in most NSCLC cell lines and tissues during cancer development [76,87]. Meanwhile, ERβ showed the highest score among the candidate nuclear receptors interacting with CLPTM1L according to the mass spectrographic analysis.…”