Preclinical data support that PI3K and AKT can phosphorylate ERα at Ser167 to activate ERα independently in the absence of estrogen, so the interaction between ER and PI3K/AKT/mTOR pathway hyperactivation causes breast cancer cells to lose sensitivity to endocrine therapy (Campbell et al., 2001) (Figure 2). The gene discussed is PIK3CA; the disease is breast cancer.