Context-dependent dual role of GRHL1 in triple negative and luminal B breast cancer

Abstract Background Breast cancer remains the leading cause of female cancer mortality worldwide. Triple-negative breast cancer is associated with a poor prognosis and limited therapeutic options due to the absence of well-defined molecular targets. Grainyhead-like 1 (GRHL1), an evolutionarily conserved transcription factor regulating epithelial differentiation, displays context-dependent tumor-suppressive or oncogenic roles. Methods Given the pivotal role of breast cancer stem cells in chemotherapy resistance, metastasis, and recurrence, we investigated the functional role of GRHL1 in primary patient derived breast cancer stem cells and publicly available breast cancer cell lines. Results Breast cancer subtype analysis reveals that GRHL1 mRNA expression is elevated in the Basal-like subtype. Notably, elevated GRHL1 correlates with prolonged overall survival specifically within triple-negative breast cancer, whereas lower expression predicts favorable outcomes in other subtypes. Depletion of GRHL1 in triple-negative breast cancer cell lines enhanced self-renewal while reducing migratory capacity and epithelial–mesenchymal transition marker expression. Conversely, GRHL1 overexpression suppressed self-renewal and increased migration and epithelial–mesenchymal transition markers. In a luminal B breast cancer stem cell line, GRHL1 exerted opposing effects, with overexpression enhancing stemness features and depletion leading to a reduction thereof. Conclusions These findings emphasize the context-dependent dual role of GRHL1, highlighting its subtype-specific influence on breast cancer progression and plasticity.