The Mechanism of Steroid Hormones in Non-Small Cell Lung Cancer: From Molecular Signaling to Clinical Application

Abstract

Steroid hormones play critical roles in the development and progression of NSCLC through both genomic and non-genomic pathways. This review summarizes the expression profiles and molecular functions of estrogen, progesterone, androgen, and glucocorticoid receptors in NSCLC. Estrogen and progesterone receptors exhibit gender-specific prognostic significance, while glucocorticoid receptors influence tumor growth and immune responses. Emerging evidence supports the use of anti-estrogen therapies and glucocorticoids as adjuncts to existing treatment strategies, including immunotherapy. The crosstalk between hormone signaling and oncogenic pathways such as EGFR or immune checkpoints offers opportunities for novel combination therapies. However, challenges remain in biomarker development, drug resistance, and managing the dual effects of glucocorticoids. A deeper understanding of hormone-tumor-immune interactions is essential to optimize hormone-targeted interventions in NSCLC.

Keywords: glucocorticoids; hormone receptors; non-small cell lung cancer; steroid hormones; targeted therapy.

Figure 1

Schematic of estrogen-mediated signaling pathways in NSCLC. Estrogen exerts biological effects via ERβ-centered cascades. In the genomic pathway, the estrogen-bound ERβ dimer translocates to the nucleus, interacting with ERE or transcription factors to regulate the transcription of genes like Cyclin D1, VEGF, and Bcl-2. In the non-genomic pathway, ERβ activates cytoplasmic kinase cascades: PI3K/AKT promotes cell survival; MAPK and cAMP/PKA activate CREB for growth-related gene expression. GPER-mediated signaling triggers rapid RAS/MEK/ERK and PI3K/AKT activation for proliferation. NF-κB is linked to inflammation. (NSCLC: non-small cell lung cancer; ER: estrogen receptor; ERE: estrogen response element; VEGF: vascular endothelial growth factor; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; JNK: c-Jun N-terminal kinase; MAPK: mitogen-activated protein kinase; cAMP: cyclic adenosine monophosphate; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase; NF-κB: nuclear factor kappa B).

Figure 2

Schematic of glucocorticoid-related signaling impacts on NSCLC immunotherapy and tumor biology. In the cytoplasm, GR interaction suppresses the activation, proliferation, and function of key immune cells (T cells, NK cells, dendritic cells) via inhibiting cytokine production and metabolic pathways, reducing the anti-tumor immune capacity. In the tumor cell context, GCs enhance PD-L1 expression on tumor surfaces. PD-L1 then binds PD-1 on T cells, blocking T-cell responses. (NSCLC: non-small cell lung cancer; GR: glucocorticoid receptor; NK: natural killer; GCs: glucocorticoids; PD-L1: programmed death ligand 1; PD-1: programmed death receptor 1).