The effect of HIF-1α inhibition in breast cancer cells prior to doxorubicin treatment under conditions of normoxia and hypoxia

Background: Oxygen deprivation is a key hallmark within solid tumours that contributes to breast-tumour pathophysiology. Under these conditions, neoplastic cells activate several genes, regulated by the HIF-1 transcription factor, which alters the tumour microenvironment to promote survival - including resistance to cell death in therapeutic attempts such as doxorubicin (Dox) treatment. Methods: We investigated HIF-1 alpha as a therapeutic target to sensitize breast cancer cells to Dox treatment. Under both normoxic (21% O-2) and hypoxic (similar to 0.1% O-2) conditions, the HIF-1 inhibitor, 2-methoxyestradiol (2-ME), was investigated as an adjuvant for its ability to alter MCF-7 cell viability, apoptosis, autophagy and molecular pathways which are often associated with increased cell survival. Results: Here we observed that an inverse relationship between HIF-1 alpha and apoptosis exists and that Dox promotes autophagy under hypoxic conditions. Although adjuvant therapy with 2-ME induced an antagonistic effect in breast cancer cells, upregulated HIF-1 alpha expression in a hypoxic environment promotes treatment resistance and this was attenuated once HIF-1 alpha gene expression was silenced. Conclusion: Therefore, highlighting the identification of possible hypoxia-targeting therapies for breast cancer patients can be beneficial by promoting more favourable treatment responses.

Automated summary

This study explores the role of HIF-1 alpha in breast cancer cells under hypoxic conditions and its impact on cell survival, apoptosis, and autophagy. The results suggest that targeting HIF-1 alpha may sensitize breast cancer cells to doxorubicin treatment and improve treatment responses. Silencing the HIF-1 alpha gene expression attenuates treatment resistance in a hypoxic environment.