Abstract 2303: The potential role of nonhypoxic HIF-1 in HER2-mediated aromatase inhibitor resistant breast cancer
Authors: Kazi Armina A. , Gilani Rabia A. , Brodie Angela H. 
Published: June 2012

Abstract
Although aromatase inhibitors (AIs; i.e., letrozole) 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 epidermal growth factor receptor (EGFR)/HER2. The mechanism by which HER2 is involved in AI resistance remains 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 and targets for therapy. One such factor may be HIF-1, a heterodimeric transcription factor made up of an inducible alpha (α) subunit and a constitutively expressed beta (β) subunit. HIF-1 regulates genes important for cell survival, metabolic adaptation, and angiogenesis. Oxygen (O2) tension is a well-known regulator of HIF-1α, but other factors independent of O2 can also regulate it. Previous studies have shown that transfecting HER2 into cells and activation of kinase pathways increase HIF-1α expression and/or activity. Unlike the well-studied role of hypoxia-regulated HIF-1α in a variety of cancers, nonhypoxic regulation of HIF-1α and its role in cancer remains largely unclear. Here we have investigated HIF1α in AI resistance. Preliminary results indicate that basal HIF-1α protein expression is 3-fold (p&lt;0.01) higher in letrozole-resistant, long term letrozole- treated MCF-7Ca (LTLTCa) cells than in their parental MCF-7Ca cells under nonhypoxic conditions. The higher expression in LTLTCa cells is likely due to increased protein synthesis for several reasons. LTLTCa cells do not have higher HIF-1α mRNA levels than MCF-7Ca cells, nor is the mRNA more stable. Also, compared to basal HIF-1α protein that rapidly degrades within 1 h of treatment with protein synthesis inhibitor cycloheximide, HIF-1α protein expression after treatment with HIF-1α stabilizer CoCl2 is increased 2.8-fold (p&lt;0.001) and is resistant to degradation. Also, HIF-1α protein expression is significantly decreased (0.05-fold vs. vehicle, p&lt;0.01) in LTLTCa cells treated with either HER2 inhibitor lapatinib or PI3K/Akt pathway inhibitor LY294002, which indicates a role for HER2 activated-PI3K/Akt pathway. Lastly, breast cancer resistance protein (BCRP) mRNA and protein expression is 3-fold higher in LTLTCa cells vs. MCF-7Ca cells (p &lt;0.01), and its expression levels are increased and decreased by CoCl2 and lapatinib, respectively. Lapatinib, additionally, decreases basal HIF-1α binding to the BCRP promoter. These results suggest that a mechanism of resistance to AIs may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, an efflux transporter protein and stem cell marker implicated in chemoresistance.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2303. doi:10.1158/1538-7445.AM2011-2303