title: Anticipatory estrogen activation of the unfolded protein response is linked to cell proliferation and poor survival in estrogen receptor α-positive breast cancer.
abstract: In response to cell stress, cancer cells often activate the endoplasmic reticulum (EnR) stress sensor, the unfolded protein response (UPR). Little was known about the potential role in cancer of a different mode of UPR activation, anticipatory activation of the UPR prior to accumulation of unfolded protein or cell stress. We show that estrogen, acting via estrogen receptor α (ERα), induces rapid anticipatory activation of the UPR, resulting in increased production of the antiapoptotic chaperone BiP/GRP78, preparing cancer cells for the increased protein production required for subsequent estrogen-ERα-induced cell proliferation. In ERα-containing cancer cells, the estrogen, 17β-estradiol (E2) activates the UPR through a phospholipase C γ (PLCγ)-mediated opening of EnR IP3R calcium channels, enabling passage of calcium from the lumen of the EnR into the cytosol. siRNA knockdown of ERα blocked the estrogen-mediated increase in cytosol calcium and UPR activation. Knockdown or inhibition of PLCγ, or of IP3R, strongly inhibited the estrogen-mediated increases in cytosol calcium, UPR activation and cell proliferation. E2-ERα activates all three arms of the UPR in breast and ovarian cancer cells in culture and in a mouse xenograft. Knockdown of ATF6α, which regulates UPR chaperones, blocked estrogen induction of BiP and strongly inhibited E2-ERα-stimulated cell proliferation. Mild and transient UPR activation by estrogen promotes an adaptive UPR response that protects cells against subsequent UPR-mediated apoptosis. Analysis of data from ERα(+) breast cancers demonstrates elevated expression of a UPR gene signature that is a powerful new prognostic marker tightly correlated with subsequent resistance to tamoxifen therapy, reduced time to recurrence and poor survival. Thus, as an early component of the E2-ERα proliferation program, the mitogen estrogen, drives rapid anticipatory activation of the UPR. Anticipatory activation of the UPR is a new role for estrogens in cancer cell proliferation and resistance to therapy.
authors.affiliation: 1] Department of Biochemistry, University of Illinois, Urbana, IL, USA [2] College of Medicine, University of Illinois, Urbana, IL, USA.
authors.forename: N
authors.initials: N
authors.lastname: Andruska
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: 1] College of Medicine, University of Illinois, Urbana, IL, USA [2] Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, USA [3] University of Illinois Cancer Center, Urbana, IL, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Helferich
authors.affiliation: 1] Department of Biochemistry, University of Illinois, Urbana, IL, USA [2] College of Medicine, University of Illinois, Urbana, IL, USA [3] University of Illinois Cancer Center, Urbana, IL, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053208:Kaplan-Meier Estimate; D061986:MCF-7 Cells; D008819:Mice, Nude; D018613:Microscopy, Confocal; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013629:Tamoxifen / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; C506487:ESR1 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; D047628:Estrogen Receptor alpha; D004967:Estrogens; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D013629:Tamoxifen; D004958:Estradiol