Our laboratory aims to elucidate the molecular mechanism of gene transcriptional regulation and its dysregulation in breast cancer. Breast cancer is the most common type of cancer and one of the leading causes of death among Western women. A vast majority (75%) of breast cancer has been found to express estrogen receptor (ER), which is the key mediator of estrogen functions and plays prominent roles in breast tumorigenesis and drug resistance. Anti-estrogens, such as tamoxifen, have been widely used in the treatment of ER-positive breast cancer, but acquired resistance and severe side effect on other estrogen-responsive tissues has greatly limited their usefulness. Hence, further development of novel strategies to selectively block estrogen signaling pathways is urgently needed. Our recent work has established MED1 (Mediator Subunit 1) as a key tissue-specific transcriptional coactivator in mediating estrogen receptor functions in both normal mammary gland development and breast cancer. Significantly, MED1 has been reported to be overexpressed or amplified in a high percentage (40% to 50%) of human breast cancers. Intriguingly, recent studies also discovered an increased frequency of MED1 mutations in metastasis “seeding” circulating tumor cells following endocrine therapies [Nature (2013) 497:108]. We are currently continuing to determine the role of MED1 and its associated proteins in breast cancer by using a combination of state-of-art biochemical, molecular and cellular techniques, as well as mouse genetic approaches with our newly generated MED1 mutant knockin, conditional knockout and overexpression models. Most recently, we have also started developing RNA nanotechnology-based strategies to target MED1 to explore its therapeutic potentials. Through these investigations, our ultimate goal is to provide novel insights and potential therapeutic targets for better diagnosis, prognosis and individualized treatment of human breast cancer.