Based on this, a proposed model of acquired AI-resistance may involve the following scenario: under non-hypoxic conditions, when the breast cancer cell population and tumor size have been reduced by letrozole treatment and prior to significant tumor hypoxia, a switch from ERα- to growth factor (for example, HER2)-mediated signaling occurs via PI3K/Akt and mTOR, which leads to increased HIF-1α expression and activation of HIF-1 target genes (for example, BCRP) that contribute to AI resistance (Figure 11). This evidence concerns the gene ESR1 and breast cancer.