The EGR1/caspase-14/HIF-1α axis mediates tamoxifen resistance in MCF-7 breast cancer cells.

Abstract

Breast cancer therapy is compromised by widespread tamoxifen resistance. The modulatory role of Caspase14 in the early growth response protein 1 (EGR1)/hypoxia-inducible factor 1-alpha (HIF-1α) axis in this context is unclear. We investigated how Caspase14 regulates EGR1/HIF-1α to promote 4-hydroxytamoxifen (4-OHT) resistance in MCF7 cells using cell-based genetic and biochemical assays (small-interference RNA knockdown, plasmid overexpression, Western blotting, qPCR, IC50 assays, and Chromatin immunoprecipitation experiments) across multiple independent experiments. Caspase14 expression correlated with resistance, with IC₅₀ rising from 0.178 µM to 1.575 µM in resistant variants. EGR1 knockdown reduced Caspase14 and downstream targets GLUT3 and BCRP, implicating EGR1 as a key mediator. Resistant cells displayed elevated HIF-1α that enhanced metabolism and migration, further supporting a role in drug resistance. These data indicate that Caspase14 promotes survival, proliferation, and metabolic reprogramming in resistant MCF7 cells via the EGR1/HIF-1α pathway. Our findings reveal a mechanistic link between Caspase14 and endocrine therapy resistance and nominate Caspase14 as a therapeutic target to overcome tamoxifen resistance, with potential translational relevance.