title: Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine therapy-resistant breast cancer.
abstract: Tamoxifen, a selective estrogen receptor (ER) modulator (SERM), remains a frontline clinical therapy for patients with ERα-positive breast cancer. However, the relatively rapid development of resistance to this drug in the metastatic setting remains an impediment to a durable response. Although drug resistance likely arises by many different mechanisms, the consensus is that most of the implicated pathways facilitate the outgrowth of a subpopulation of cancer cells that can either recognize tamoxifen as an agonist or bypass the regulatory control of ERα. Notable in this regard is the observation here and in other studies that expression of anterior gradient homology 2 (AGR2), a known proto-oncogene and disulfide isomerase, was induced by both estrogen (17β-estradiol, E2) and 4-hydroxytamoxifen (4OHT) in breast cancer cells. The importance of AGR2 expression is highlighted here by the observation that (i) its knockdown inhibited the growth of both tamoxifen-sensitive and -resistant breast cancer cells and (ii) its increased expression enhanced the growth of ERα-positive tumors in vivo and increased the migratory capacity of breast cancer cells in vitro. Interestingly, as with most ERα target genes, the expression of AGR2 in all breast cancer cells examined requires the transcription factor FOXA1. However, in tamoxifen-resistant cells, the expression of AGR2 occurs in a constitutive manner, requiring FOXA1, but loses its dependence on ER. Taken together, these data define the importance of AGR2 in breast cancer cell growth and highlight a mechanism where changes in FOXA1 activity obviate the need for ER in the regulation of this gene.
  
  
  CONCLUSIONS
  These findings reveal the transcriptional interplay between FOXA1 and ERα in controlling AGR2 during the transition from therapy-sensitive to -resistant breast cancer and implicate AGR2 as a relevant therapeutic target.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Tricia M
authors.initials: TM
authors.lastname: Wright
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Wardell
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Jeff S
authors.initials: JS
authors.lastname: Jasper
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: James P
authors.initials: JP
authors.lastname: Stice
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, North Carolina. donald.mcdonnell@duke.edu.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D013629:Tamoxifen / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C502296:AGR2 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C000715470:MAS1 protein, human; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D000090063:Proto-Oncogene Mas; D013629:Tamoxifen; D004958:Estradiol
references.citation: J Proteome Res. 2011 Oct 7;10(10):4567-78
references.pmid: 21936522
references.citation: Gene. 2013 Apr 10;518(1):209-14
references.pmid: 23246976
references.citation: Mol Endocrinol. 2012 Jul;26(7):1235-48
references.pmid: 22570330
references.citation: Oncology. 2009;77 Suppl 1:23-37
references.pmid: 20130429
references.citation: Oncogene. 2010 Aug 26;29(34):4838-47
references.pmid: 20531310
references.citation: Am J Pathol. 2009 Nov;175(5):1848-57
references.pmid: 19834055
references.citation: Cancer Lett. 2013 Jun 10;333(2):187-93
references.pmid: 23354592
references.citation: Nat Genet. 2013 Oct;45(10):1113-20
references.pmid: 24071849
references.citation: Bioinformatics. 2011 Nov 15;27(22):3206-8
references.pmid: 21903630
references.citation: Mol Endocrinol. 2008 Jan;22(1):65-77
references.pmid: 17872378
references.citation: Cancer. 2008 Nov 1;113(9):2385-97
references.pmid: 18819158
references.citation: Biostatistics. 2010 Apr;11(2):242-53
references.pmid: 20097884
references.citation: Nature. 2012 Mar 28;483(7391):603-7
references.pmid: 22460905
references.citation: Endocr Relat Cancer. 2003 Jun;10(2):267-77
references.pmid: 12790788
references.citation: Nature. 2012 Jan 04;481(7381):389-93
references.pmid: 22217937
references.citation: Clin Cancer Res. 2009 Mar 15;15(6):2181-91
references.pmid: 19276290
references.citation: Carcinogenesis. 2012 Jun;33(6):1178-86
references.pmid: 22467239
references.citation: Cancer Res. 2001 Apr 1;61(7):2917-22
references.pmid: 11306468
references.citation: Curr Opin Pharmacol. 2010 Dec;10(6):620-8
references.pmid: 20926342
references.citation: Zhonghua Bing Li Xue Za Zhi. 2008 Feb;37(2):109-13
references.pmid: 18681322
references.citation: Cancer Res. 2008 Oct 1;68(19):7811-8
references.pmid: 18829536
references.citation: Cancer Res. 2010 Jan 1;70(1):240-8
references.pmid: 20048076
references.citation: Breast Cancer Res. 2013 Apr 24;15(2):204
references.pmid: 23635006
references.citation: Clin Cancer Res. 2006 Mar 15;12(6):1728-34
references.pmid: 16551856
references.citation: Nat Genet. 2011 Jan;43(1):27-33
references.pmid: 21151129
references.citation: Clin Cancer Res. 2013 May 1;19(9):2420-31
references.pmid: 23536434
references.citation: Exp Mol Med. 2011 Feb 28;43(2):91-100
references.pmid: 21200134
references.citation: Breast Cancer Res. 2010;12(3):R32
references.pmid: 20525379
references.citation: Genome Res. 2003 Nov;13(11):2498-504
references.pmid: 14597658
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1160-7
references.pmid: 19204204
references.citation: Cancer Res. 2008 Jan 15;68(2):492-7
references.pmid: 18199544
references.citation: J Clin Oncol. 2006 Oct 1;24(28):4611-9
references.pmid: 17008703
references.citation: Dev Biol. 2012 Sep 15;369(2):249-60
references.pmid: 22819674
references.citation: Br J Cancer. 2006 Apr 10;94(7):1057-65
references.pmid: 16598187
references.citation: Nature. 2008 Dec 4;456(7222):663-6
references.pmid: 19005469
references.citation: Endocrinology. 2003 Mar;144(3):1032-44
references.pmid: 12586780
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Genes Immun. 2006 Jan;7(1):11-8
references.pmid: 16222343