BRCA1 mainly acts as a tumor suppressor and BRCA1 mutation correlates with increased cancer risk. Although it is well recognized that BRCA1 related tumorigenesis is mainly caused by the increased DNA damage and decreased genome stability, it is not clear that why BRCA1 related patients have higher risk for cancer development mainly in estrogen responsive tissues such as breast and ovary. Recent studies suggested that BRCA1 and E-ER (estrogen and estrogen receptor) signaling synergistically regulate the mammary epithelial cell proliferation and differentiation. In this current presentation, we reviewed the correlation between mammary gland epithelial cell transformation and the status of BRCA1 and ER. Then the mechanisms of BRCA1 and E-ER interaction at both gene transcription level and protein-protein interaction level are discussed. Furthermore, the tumorigenic mechanisms are discussed by focusing on the synergistic effect of BRCA1 and E-ER on cell metabolism, ROS management, and antioxidant activity in mammary gland epithelial cells. Also, the possibility of cell de-differentiation promoted by coordinated effect between BRCA1 mutation and E-ER signal is explored. Together, the currently available evidences suggest that BRCA1 mutation and E-ER signal together, contribute to breast tumorigenesis by providing the metabolic support for cancer cell growth and even may directly be involved in promoting the de-differentiation of cancer-prone epithelial cells. © Ivyspring International Publisher.