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

Abstract

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-1ɑ as a therapeutic target to sensitize breast cancer cells to Dox treatment. Under both normoxic (21% O₂) and hypoxic (∼0.1% O₂) 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-1ɑ 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-1ɑ expression in a hypoxic environment promotes treatment resistance and this was attenuated once HIF-1ɑ 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.

Keywords: Apoptosis; Autophagy; Breast cancer; Doxorubicin; HIF-1α; Hypoxia; Normoxia.