title: Interplay between steroid hormone activation of the unfolded protein response and nuclear receptor action.
abstract: To identify new pathways of estrogen action and novel estrogen receptor α (ERα) biomodulators, we performed high throughput screening and used follow on assays and bioinformatics to identify small molecule ERα inhibitors with a novel mode of action. These studies led to identification of rapid extranuclear activation of the endoplasmic reticulum stress sensor, the unfolded protein response (UPR), as a new pathway of estrogen-ERα action. Moreover, increasing evidence indicates that the mechanism underlying anticipatory activation of the UPR is shared among steroid and peptide hormones and is conserved from insects to humans. It is likely that this newly unveiled extranuclear pathway is used by diverse mitogenic hormones to prepare cells for the increased protein folding load that will occur during subsequent cell proliferation. Demonstrating biological relevance, elevated expression of a UPR gene signature in ERα positive breast cancer is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen, tumor recurrence and poor survival. In addition, overexpression of epidermal growth factor receptor and HER2/neu is positively correlated with increased UPR activation in breast cancer. This review describes recent research that demonstrates the importance of anticipatory UPR activation in therapy resistant tumors and discusses a promising small molecule biomodulator that inhibits tumor growth by tuning this UPR signaling pathway.
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: Andruska
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Chengjian
authors.initials: C
authors.lastname: Mao
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Mara
authors.initials: M
authors.lastname: Livezey
authors.affiliation: University of Illinois Cancer Center, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: William G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA; College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA. Electronic address: djshapir@illinois.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D056811:Unfolded Protein Response / Q000235:genetics / Q000502:physiology*
chemical_list: D047628:Estrogen Receptor alpha; D066246:ErbB Receptors
keywords: Breast cancer; Cancer; Cell death; Hormone action; Steroid receptor; Unfolded protein response