By using a multi-step approach, namely, (i) siRNA screen in isogenic human mammary epithelial cell lines, (ii) shRNA screen in breast cancer cell lines, (iii) identifying hits between siRNA-shRNA screens and three independent gene essentiality screens, and (iv) drug sensitivity assay in cell lines or publicly available pan-cancer somatic mutation data, PTEN synthetic lethal genes were identified in breast cancer. This evidence concerns the gene PTEN and breast cancer.