title: Glyceollin, a novel regulator of mTOR/p70S6 in estrogen receptor positive breast cancer.
abstract: An estimated 70% of breast cancer tumors utilize estrogen receptor (ER) signaling to maintain tumorigenesis and targeting of the estrogen receptor is a common method of treatment for these tumor types. However, ER-positive (+) breast cancers often acquire drug resistant or altered ER activity in response to anti-estrogens. Here we demonstrate glyceollin, an activated soy compound, has anti-estrogen effects in breast cancers. We demonstrate through estrogen response element luciferase and phosphorylation-ER mutants that the effects of glyceollin arise from mechanisms distinct from conventional endocrine therapies. We show that glyceollin suppresses estrogen response element activity; however, it does not affect ER-alpha (α) phosphorylation levels. Additionally we show that glyceollin suppresses the phosphorylation of proteins known to crosstalk with ER signaling, specifically we demonstrate an inhibition of ribosomal protein S6 kinase, 70 kDa (p70S6) phosphorylation following glyceollin treatment. Our data suggests a mechanism for glyceollin inhibition of ERα through the induced suppression of p70S6 and demonstrates novel mechanisms for ER inhibition.
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, United States.
authors.forename: Melyssa R
authors.initials: MR
authors.lastname: Bratton
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Martin
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States.
authors.forename: Steven
authors.initials: S
authors.lastname: Elliott
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States.
authors.forename: Lyndsay V
authors.initials: LV
authors.lastname: Rhodes
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States.
authors.forename: Bridgette M
authors.initials: BM
authors.lastname: Collins-Burow
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States; Department of Pharmacology, Tulane University, New Orleans, LA, United States; The Center for Bioenvironmental Research, Tulane University, New Orleans, LA, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: McLachlan
authors.affiliation: Division of Basic Pharmaceutical Sciences, College of Pharmacy, Xavier University of Louisiana, New Orleans, LA, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Wiese
authors.affiliation: Southern Regional Research Center, U.S. Department of Agriculture, New Orleans, LA, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Boue
authors.affiliation: Department of Medicine-Section of Hematology and Medical Oncology, Tulane University, New Orleans, LA, United States; Department of Pharmacology, Tulane University, New Orleans, LA, United States; The Center for Bioenvironmental Research, Tulane University, New Orleans, LA, United States. Electronic address: mburow@tulane.edu.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Burow
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D049109:Cell Proliferation; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D036343:Pterocarpans / Q000494:pharmacology*; D020218:Response Elements; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D010936:Plant Extracts; D036343:Pterocarpans; C017343:glyceollin; D008156:Luciferases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases
keywords: Anti-estrogen; Endocrine therapy; Estrogen receptor (ER); Glyceollin; Kinase signaling; mTOR; p70S6