Cytoplasmic expression of G protein-coupled estrogen receptor 1 correlates with poor postoperative prognosis in non-small cell lung cancer

Abstract

Background: A hormonal role in the development of non-small cell lung cancer (NSCLC) has been well documented, and the classic estrogen receptors (ERs)-ERα and ERβ have been extensively investigated over the past decade. The expression of ERβ was found to be high and display biological activity in NSCLC, but anti-estrogen therapy targeting this receptor has shown limited efficacy for the disease. The third estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1/GPR30), was recently found to be highly expressed in NSCLC. Herein, we aimed to investigate the expression profile of GPER1 and correlate it with clinicopathological factors as well as postoperative prognosis in NSCLC.

Methods: We examined GPER1 and ERβ expression using immunohistochemistry among 183 NSCLC cases, including 132 lung adenocarcinoma (LUAD) with identified epidermal growth factor receptor (EGFR) mutation status and 51 squamous cell carcinoma (SCC) patients. We then conducted correlation analysis between the expression of GPER1 and clinicopathological factors and patients' postoperative prognosis.

Results: Positive expression of GPER1 was categorized into 2 main classes: nuclei-GPER1 (nGPER1) and concurrent nuclei-and cytoplasm-GPER1 (n/cGPER1), according to its subcellular localization. The LUAD with wild-type EGFR (wt-EGFR) had a higher frequency of n/cGPER1 (50%) but a lower frequency of nGPER1 (31%) when compared with those with mutated EGFR (n/cGPER1: 31%, nGPER1: 41%, respectively). The expression of GPER1, regardless of subcellular localization, was positively correlated with tumor stage and lymph node metastasis. The median recurrence-free survival (mRFS) and overall survival (OS) were significantly worse in participants with n/cGPER1 expression than in those with nGPER1 or without GPER1 expression.

Conclusions: This study revealed that GPER1 is aberrantly highly expressed and presents a unique GPER1 expression profile in NSCLC. The n/cGPER1 expression was significantly associated with EGFR mutation status, tumor stage, lymph node metastasis, and poor postoperative prognosis in NSCLC.

Keywords: G protein-coupled estrogen receptor 1 (GPER1); Non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); prognosis; recurrence-free survival (RFS).

Figure 1

Representative immunohistochemical staining pattern of GPER1. Specimens were categorized into three classes: negative for both nuclei and cytoplasm, negative; negative for cytoplasm but positive for nuclei, nGPER1; positive for both nuclei and cytoplasm, n/cGPER1. The images are shown at ×400 magnification and the scale bar indicates 50 µm. LUAD, lung adenocarcinoma; SCC, squamous cell carcinoma; GPER1, G protein-coupled estrogen receptor 1

Figure 2

Representative immunohistochemical staining of ERβ. The images are shown at ×400 magnification and the scale bar indicates 50 µm. LUAD, lung adenocarcinoma; SCC, squamous cell carcinoma; ERβ, estrogen receptor β.

Figure 3

Kaplan-Meier curve showing RFS in LUAD. RFS curves stratified by the expression of cGPER1 in patients (A) with EGFR mutation and (B) with wt-EGFR. RFS curves stratified by the expression of nGPER1 in patients (C) with EGFR mutation and (D) with wt-EGFR. RFS, recurrence-free survival; cGPER1, cytoplasm-G protein-coupled estrogen receptor 1; HR, hazard ratio; CI, confidence interval; LUAD, lung adenocarcinoma; EGFR, epidermal growth factor receptor; wt-EGFR, wild-type EGFR.

Figure 4

Kaplan-Meier curve showing RFS. RFS curves stratified by the expression of cGPER1 in SCC. RFS, recurrence-free survival; cGPER1, cytoplasm-G protein-coupled estrogen receptor 1; HR, hazard ratio; 95% CI, 95% confidence interval; SCC, squamous cell carcinoma.

Figure 5

Kaplan-Meier curve showing OS. OS curves stratified by the expression of cGPER1 in LUAD (A) and SCC (B) patients, respectively. OS, overall survival; cGPER1, cytoplasm-G protein-coupled estrogen receptor 1; HR, hazard ratio; CI, confidence interval; LUAD, lung adenocarcinoma; SCC, squamous cell carcinoma.