# The Crosstalk Mechanism of EGFR and ER in EGFR-Mutant Lung Adenocarcinoma

## TL;DR

This study explores how estrogen receptor (ER) and EGFR interact in lung cancer, showing that combining tamoxifen and EGFR inhibitors may be an effective treatment strategy.

## Contribution

The study identifies heparin-binding EGF-like growth factor as a key mediator in the crosstalk between ER and EGFR pathways in lung adenocarcinoma.

## Key findings

- Antiestrogen treatment correlates with mutant EGFR expression in lung cancer patients.
- Tamoxifen upregulates p-EGFR in EGFR-mutant lung cancer cell lines.
- Combined tamoxifen and EGFR TKI therapy inhibits p-EGFR expression in lung adenocarcinoma.

## Abstract

Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy.