Estrogen Receptor Signaling in Non-Small Cell Lung Cancer

Oestrogen receptor signalling has emerged as a critical modulator of non-small cell lung cancer (NSCLC) biology, influencing tumour initiation, progression, metastasis and therapy response. Two principal receptor isoforms, ERα and ERβ, are variably expressed in lung tumour cells and in stromal elements, where they engage both genomic and non-genomic pathways. Genomic signalling involves receptor dimerisation, DNA binding at oestrogen response elements and transcriptional regulation of genes governing cell cycle, apoptosis and invasion. Rapid, non-genomic effects are mediated through cross-talk with membrane-associated tyrosine kinases such as EGFR and fibroblast growth factor receptors, leading to activation of MAPK/ERK and PI3K/AKT pathways. In the tumour microenvironment, oestrogen receptors on cancer-associated fibroblasts, immune cells and endothelial cells reshape signalling networks that foster a pro-tumour milieu. This signalling axis underlies sex-based disparities in NSCLC incidence and outcome, as well as emerging resistance to targeted and immune therapies. Preclinical studies have demonstrated that inhibition of aromatase or ER activity can suppress NSCLC cell proliferation, reduce metastatic potential and enhance sensitivity to EGFR inhibitors and immune checkpoint blockade. These findings suggest that combining anti-oestrogen strategies with current regimens may yield tangible clinical benefit, particularly in female or never-smoker cohorts.

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Estrogen Receptor Signaling in Non-Small Cell Lung Cancer publication trend

The graph below shows the total number of articles in estrogen receptor signaling in non-small cell lung cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Estrogen receptor (ER): nuclear hormone receptor with α and β isoforms that mediates effects of oestrogens by regulating gene transcription and rapid signalling pathways.

Non-small cell lung cancer (NSCLC): the predominant group of lung malignancies encompassing adenocarcinoma, squamous cell carcinoma and large cell carcinoma.

MAPK pathway: a kinase cascade that transduces extracellular signals to promote cellular proliferation, differentiation and survival.

Cancer-associated fibroblasts (CAFs): stromal cells within the tumour microenvironment that interact with tumour cells and modulate growth, invasion and therapy response.

Tumour microenvironment (TME): the cellular and molecular milieu surrounding tumour cells, including immune cells, stromal cells and extracellular matrix.

EGFR: a receptor tyrosine kinase frequently mutated or overexpressed in NSCLC that drives proliferation and survival signalling.

References

1. TFAP2A drives non-small cell lung cancer (NSCLC) progression and resistance to targeted therapy by facilitating the ESR2-mediated MAPK pathway. Cell Death Discovery (2024).
2. New Perspectives on Sex Steroid Hormones Signaling in Cancer-Associated Fibroblasts of Non-Small Cell Lung Cancer. Cancers (2023).
3. Influence of Estrogen on the NSCLC Microenvironment: A Comprehensive Picture and Clinical Implications. Frontiers in Oncology (2020).
4. Interaction between the estrogen receptor and fibroblast growth factor receptor pathways in non-small cell lung cancer. Oncotarget (2017).
5. Hormonal receptors in lung adenocarcinoma: expression and difference in outcome by sex. Oncotarget (2016).
6. Estrogen receptors promote NSCLC progression by modulating the membrane receptor signaling network: a systems biology perspective. Journal of Translational Medicine (2019).