Investigating the Regulation and Potential Role of Nonhypoxic Hypoxia- Inducible Factor 1 (HIF-1) in Aromatase Inhibitor Resistant Breast Cancer.

摘要

Although aromatase inhibitors (AIs) have been shown to be highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Studies suggest that resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor-mediated pathways, such as human epidermal growth factor receptor-2 (HER2). The mechanism by which HER2 is involved in AI resistance remains mostly unclear. It is, therefore, important to elucidate the HER2-mediated pathway that contributes to AI resistance, and to identify other relevant factors involved that can be used as biomarkers of AI resistance or targets for therapy. One such factor may include HIF-1, a heterodimeric transcription factor made up of an inducible alpha subunit and a constitutively expressed beta subunit. Unlike the well-studied role of hypoxia-regulated HIF-1 in a variety of cancers, nonhypoxic regulation of HIF-1 and its role in cancer remains largely unclear. Here we have investigated HIF1 in AI resistance . Results indicate that basal nonhypoxic HIF-1 protein expression (1) is higher in AI resistant cells than in their AI-sensitive parental cells, (2) is regulated by HER2, and in turn (3) regulates cancer stem cell markers and cancer stem cell characteristics that may contribute to drug resistance. Lastly, EZN-2968, a specific HIF-1 RNA antagonist currently in phase 1 clinical trials has shown potential in treating aromatase inhibitor resistance.