title: 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.
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.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Xianzhou
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America; Integrative Molecular and Biomedical Sciences Graduate Program, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Mingkun
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jianwei
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: David M
authors.initials: DM
authors.lastname: Lonard
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Qin
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jianming
authors.initials: J
authors.lastname: Xu
authors.affiliation: Lester & Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Bert W
authors.initials: BW
authors.lastname: O'Malley
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, Houston, Texas, United States of America; Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D002018:Bufanolides / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D056921:Nuclear Receptor Coactivator 3 / Q000378:metabolism*; D011355:Prodrugs / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D002018:Bufanolides; D011355:Prodrugs; D011960:Receptors, Estrogen; D056921:Nuclear Receptor Coactivator 3; C022777:bufalin