Overall, this study provides novel evidence that non-hypoxic HIF-1α is inherently expressed in AI-resistant cells, upregulated by HER2-PI3K/Akt-mTOR pathway and is an important factor in letrozole-resistant breast cancer cells, regulating target genes such as BCRP and regulating AI responsiveness and cancer stem cell characteristic expression. This evidence concerns the gene ERBB2 and breast cancer.