Targeting EPAS-1/HIF-2α Pathway to Address Endocrine Resistance in Luminal A Type Breast Cancer.

BACKGROUND: Tamoxifen is most often used as the first treatment for luminal A breast cancer; however, one-third of the patients are resistant to it. Numerous studies have shown that hypoxia contributes to drug resistance and is related to poor clinical outcomes. Despite this, little is known regarding the key hypoxic mediators involved in tamoxifen resistance. METHODS: We performed a comprehensive multi-omics analysis using publicly available transcriptomics and whole-exome sequencing data from tamoxifen-sensitive and tamoxifen-resistant luminal A breast cancer patient samples. EPAS1 was identified as a key hypoxic mediator linked to endocrine resistance in luminal A breast cancer. In vitro assays, including Western blotting, hypoxia detection assays, and CCK8 assays, were conducted to validate the association between EPAS1 expression and tamoxifen resistance in cell lines. Additionally, we tested the effect of PT2977 (Belzutifan), an EPAS1 inhibitor, as a potential treatment for tamoxifen resistance using tamoxifen-resistant and control cells, followed by validation in xenograft models of tamoxifen-resistant tumours. RESULTS: Patient and cell line data revealed that EPAS1 is significantly upregulated in tamoxifen-resistant luminal A breast cancer, which is associated with poor survival outcomes and an altered tumour microenvironment. Further investigation using tamoxifen-resistant cell lines confirmed elevated EPAS1 expression levels. In vitro treatment with the EPAS1 inhibitor PT2977 resulted in a significant decrease in cell viability and modulated hypoxia-related pathways, indicating a potential therapeutic effect. Furthermore, in vivo studies showed that PT2977 reduced the growth of tamoxifen-resistant cells under the experimental conditions used. CONCLUSION: This study suggests that PT2977, by targeting the hypoxic gene EPAS1, has the potential to inhibit the growth of tamoxifen-resistant luminal A breast cancer. However, while PT2977 demonstrated effectiveness in reducing tumour growth under the experimental conditions used, further studies are necessary to evaluate its role in overcoming hormone resistance and to explore its therapeutic applicability in broader clinical settings and other cancer subtypes.