Breast cancer remains second only to skin cancer as the most common cancer among women in the United States. The American Cancer Society predicts over 225,000 new diagnoses and about 40,000 deaths in the US from breast cancer in 2013, second in women only to lung cancer deaths. Adjuvant and neoadjuvant chemotherapies for breast cancer are an integral part of the treatment regimen for many breast cancer patients, with many drugs and combinations of drugs in current clinical use. Many of these drugs target proliferative mechanisms in rapidly dividing cancer cells, while others interfere with hormone signaling or other signal transduction pathways. Small molecule inhibitors of epigenetic regulatory proteins as therapeutics for human disease have been validated for treatment of other cancers and remain a rapidly expanding area of research. Here we propose to identify small molecule inhibitors against a previously untargeted epigenetic regulator that is involved in controlling genomic DNA accessibility for transcription. BRG1 is an ATPase that is a catalytic subunit of the human SWI/SNF chromatin remodeling enzyme complex, an important regulator of chromatin structure and accessibility across the genome. Despite its initial labeling as a tumor suppressor protein in breast cancer, we have strong evidence that BRG1 is over-expressed in most human breast tumors, regardless of stage or hormone status. We find that experimentally reducing BRG1 levels in cultured breast cancer cells reduces their rate of proliferation in tissue culture and greatly reduces, and in some cases prevents, tumor formation when cancer cells are orthotopically implanted in mouse mammary fat pads. The mechanism for the decrease in cell proliferation and tumor initiation is a general requirement for BRG1 in the expression of enzymes necessary for lipid, and specifically, fatty acid, synthesis. Importantly, cells with decreased BRG1 levels show increased susceptibility to both standard chemotherapeutic agents used in breast cancer treatment and to inhibitors of lipid synthesis. We offer the BRG1 chromatin remodeling enzyme as an important new target for breast cancer therapy. We will develop and optimize high-throughput, high-content microscopy assays for the discovery of small molecule BRG1 inhibitors. These will be novel candidate drugs for epigenetic breast cancer chemotherapy.
Our proposed studies will build on our observations that the chromatin remodleing enzyme BRG1 is overexpressed in most primary breast tumors, that knockdown of BRG1 results in reduced cell proliferation in culture and reduced tumor growth in vivo, and that breast tumor cells with experimentally reduced levels of BRG1 are more susceptible to chemotherepeutic agents currently used for breast cancer treatment. Our proposed studies will translate these basic science findings toward clinical practice by utilizing high-throughput, high-content microscopy screens to identify compounds that interfere with BRG1 function. These BRG1 inhibitors will be novel candidate drugs for the treatment of breast cancer and may also be valuable reagents for probing the role of chromatin remodeling in breast cancer.
|Wu, Qiong; Lian, Jane B; Stein, Janet L et al. (2017) The BRG1 ATPase of human SWI/SNF chromatin remodeling enzymes as a driver of cancer. Epigenomics 9:919-931|
|Nickerson, Jeffrey A; Wu, Qiong; Imbalzano, Anthony N (2017) Mammalian SWI/SNF Enzymes and the Epigenetics of Tumor Cell Metabolic Reprogramming. Front Oncol 7:49|
|Gerstenberger, Brian S; Trzupek, John D; Tallant, Cynthia et al. (2016) Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit. J Med Chem 59:4800-11|
|Wu, Qiong; Madany, Pasil; Dobson, Jason R et al. (2016) The BRG1 chromatin remodeling enzyme links cancer cell metabolism and proliferation. Oncotarget 7:38270-38281|