In this report, we used p16;Brca1 and p18;Brca1 double-mutant mammary tumors and human BRCA1 mutant breast cancer patient-derived xenografts (PDX) to determine the function and mechanism of estrogen in promoting ER-negative BRCA1-deficient tumor initiation and progression. The gene discussed is CDKN2C; the disease is breast carcinoma.