Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR)-S6 kinase (S6K) signaling (in short: PI3K signaling) is upregulated in 25% of human breast cancers and has been associated with resistance to endocrine as well as HER2 directed therapy [1–3]. This evidence concerns the gene RPS6KB1 and breast cancer.