Steroid Receptor Coactivator-3 (SRC-3/AIB1) as a Novel Therapeutic Target in Triple Negative Breast Cancer and Its Inhibition with a Phospho-Bufalin Prodrug
Year: 2015
Type: article
Abstract: Triple negative breast cancer (TNBC) has the poorest prognosis of all types of breast cancer and currently lacks efficient targeted therapy. Chemotherapy is the traditional standard-of-care for TNBC, but is frequently accompanied by severe side effects. Despite the fact that high expression of steroid receptor coactivator 3 (SRC-3) is correlated with poor survival in estrogen receptor positive breast cancer patients, its role in TNBC has not been extensively investigated. Here, we show that high expression of SRC-3 correlates with both poor overall survival and post progression survival in TNBC patients, suggesting that SRC-3 can serve as a prognostic marker for TNBC. Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility. However, because bufalin has minimal water solubility, its in vivo application is limited. Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration. In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.
Source: PLoS ONE
Institution: Baylor College of Medicine
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: Susan G. Komen for the Cure, Prostate Cancer Foundation, Welch Foundation, Cancer Prevention and Research Institute of Texas, John S. Dunn Foundation, Rice University, Dan L. Duncan Cancer Center, Baylor College of Medicine, John S. Dunn Gulf Coast Consortium for Chemical Genomics, National Institutes of Health, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Awards: Recruitment of First-Time, Tenure-Track Faculty Members, G1448800156, G150383853, The Role of SRC-1 in Breast Cancer, Development of small molecule inhibitors that target the oncogenic SRC-3 coactivator and their characterization as novel anti-cancer agents, G2477085926, P5: Characterization of Nuclear Receptors and Coregulators in Breast Cancer Mouse Models as Targets for New Therapeutic Development, G375257059, G5180243502, Small Molecule Src-2 Antagonists as Regulators of Sertoli Cell Function and Male, Genetic and Metabolic Fingerprints of Coativators "Program Project", G6430351441, G7419161810, G771426518, G7806667152, G9000017008, G9000265539, G9000278845, G927851889
OpenAlex ID: W2193346008