title: Acquisition of estrogen independence induces TOB1-related mechanisms supporting breast cancer cell proliferation.
abstract: Resistance to therapies targeting the estrogen pathway remains a challenge in the treatment of estrogen receptor-positive breast cancer. To address this challenge, a systems biology approach was used. A library of small interfering RNAs targeting an estrogen receptor (ER)- and aromatase-centered network identified 46 genes that are dispensable in estrogen-dependent MCF7 cells, but are selectively required for the survival of estrogen-independent MCF7-derived cells and multiple additional estrogen-independent breast cancer cell lines. Integration of this information identified a tumor suppressor gene TOB1 as a critical determinant of estrogen-independent ER-positive breast cell survival. Depletion of TOB1 selectively promoted G1 phase arrest and sensitivity to AKT and mammalian target of rapmycin (mTOR) inhibitors in estrogen-independent cells but not in estrogen-dependent cells. Phosphoproteomic profiles from reverse-phase protein array analysis supported by mRNA profiling identified a significant signaling network reprogramming by TOB1 that differed in estrogen-sensitive and estrogen-resistant cell lines. These data support a novel function for TOB1 in mediating survival of estrogen-independent breast cancers. These studies also provide evidence for combining TOB1 inhibition and AKT/mTOR inhibition as a therapeutic strategy, with potential translational significance for the management of patients with ER-positive breast cancers.
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.|Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
authors.forename: R E
authors.initials: RE
authors.lastname: Nasto
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Varghese
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Jablonski
authors.affiliation: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.|Kazan Federal University, Kazan, Russia.
authors.forename: I G
authors.initials: IG
authors.lastname: Serebriiskii
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Surana
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Calvert
authors.affiliation: Biostatistics Center, George Washington University, Washington, DC, USA.
authors.forename: I
authors.initials: I
authors.lastname: Bebu
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: J
authors.initials: J
authors.lastname: Murray
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: M
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: R
authors.identifier: http://orcid.org/0000-0002-1555-4431
authors.initials: R
authors.lastname: Riggins
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ressom
authors.affiliation: Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, VA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Petricoin
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: R
authors.identifier: http://orcid.org/0000-0002-9278-0854
authors.initials: R
authors.lastname: Clarke
authors.affiliation: Program in Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Golemis
authors.affiliation: Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, DC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D061986:MCF-7 Cells; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; C098669:TOB1 protein, human; D025521:Tumor Suppressor Proteins