The Nuclear Receptor Program is a network of 20 NIH funded basic scientists focused on understanding the contribution of nuclear receptor transcription factor and chromatic modifying coregulator function to cancer development. Members have a total of $14,612,144 in peer-reviewed research support, $4,167,979 of which is from NCI and the remainder from other NIH institutes, the Department of Defense, and cancer foundation funds. Members of the Program have a strong record of both intraprogramatic collaboration and interprogramatic interactions with both basic and clinical programs throughout the cancer center. During the last three years, members published 202 peer reviewed manuscripts of which 39% were the result of intraprogrammatic interactions and 34% from interrogrammatic publications. A major goal to identify novel therapeutic targets among members of the nuclear receptor superfamily and nuclear receptor interacting coregulator proteins for prevention of and therapeutic intervention in cancer. To achieve this goal, we have adopted an integrative approach with three central components: 1) nuclear receptor and coregulator discovery and analysis of their mechanisms of regulation of cellular homeostasis, 2) preclinical assessment of their roles in cancer development using genetically manipulated mouse model systems, and 3) A translational component involving interaction with clinical programs to rapidly transfer new information into receptor profiling and assessment of therapeutic potential in human cancers. Major accomplishments include elucidation of a breast cancer cell selective posttranslational code that is responsible for overexpression of the pi60 coactivator I breast cancer cells, SRC-3 in breast cancer cells;identification of a critical role of coactivators SRC-1 and SRC-3 in breast and prostate cancer metastases;discovery of the orphan nuclear receptors, NR4A1 and NR4A3 as novel tumor suppressors of acute myeloid leukemia and discovery of their widespread gene silencing in human AML patients regardless of genetic heterogeneity;and discovery of the orphan COUP-TFII as a potent driver of epithelial tumor associated angiogenesis and metastasis.
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