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{{Infobox_gene}}
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'''Anterior gradient protein 2 homolog''' (AGR-2), also known as '''secreted cement gland protein XAG-2 homolog''', is a [[protein]] that in humans is encoded by the ''AGR2'' [[gene]]. Anterior gradient homolog 2 was originally discovered in ''[[Xenopus laevis]]''.<ref name="entrez">{{cite web | title = Entrez Gene: AGR2 anterior gradient homolog 2 (Xenopus laevis)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10551| accessdate = }}</ref> In ''Xenopus'' AGR2 plays a role in cement gland differentiation,<ref name="pmid9533957">{{cite journal |vauthors=Aberger F, Weidinger G, Grunz H, Richter K | title = Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2 | journal = Mech. Dev. | volume = 72 | issue = 1–2 | pages = 115–30 |date=March 1998  | pmid = 9533957 | doi = 10.1016/S0925-4773(98)00021-5 }}</ref> but in human cancer cell lines high levels of AGR2 correlate with downregulation of the [[p53]] response,<ref name="pmid14967811">{{cite journal |vauthors=Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, Kernohan N, Hupp TR | title = The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage | journal = Mol. Cell. Proteomics | volume = 3 | issue = 6 | pages = 534–47 |date=June 2004  | pmid = 14967811 | doi = 10.1074/mcp.M300089-MCP200 }}</ref> cell migration, and cell transformation.<ref name="Wang, Z">{{cite journal |vauthors=Wang Z, Hao Y, Lowe AW | title = The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation | journal = Cancer Res. | volume = 68 | issue = 2 | pages = 492–7 |date=January 2008  | pmid = 18199544 | doi = 10.1158/0008-5472.CAN-07-2930  }}</ref> However, there have been other observations that AGR2 can repress growth and proliferation.<ref name = "Bu_2011" />
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== Discovery in ''Xenopus laevis''==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Anterior gradient homolog 2 (Xenopus laevis)
| HGNCid = 328
| Symbol = AGR2
| AltSymbols =; AG2; GOB-4; HAG-2; XAG-2
| OMIM = 606358
| ECnumber = 
| Homologene = 4674
| MGIid = 1344405
| GeneAtlas_image1 = PBB_GE_AGR2_209173_at_tn.png
| Function =
| Component =
| Process =
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 10551
    | Hs_Ensembl = ENSG00000106541
    | Hs_RefseqProtein = NP_006399
    | Hs_RefseqmRNA = NM_006408
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 7
    | Hs_GenLoc_start = 16797963
    | Hs_GenLoc_end = 16811133
    | Hs_Uniprot = O95994
    | Mm_EntrezGene = 23795
    | Mm_Ensembl = ENSMUSG00000020581
    | Mm_RefseqmRNA = NM_011783
    | Mm_RefseqProtein = NP_035913
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 12
    | Mm_GenLoc_start = 36503173
    | Mm_GenLoc_end = 36514346
    | Mm_Uniprot = O88312
  }}
}}
'''Anterior gradient homolog 2 (Xenopus laevis)''', also known as '''AGR2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: AGR2 anterior gradient homolog 2 (Xenopus laevis)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=10551| accessdate = }}</ref>


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The ''[[Xenopus laevis]]'' anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos.<ref name="Sive_1989">{{cite journal |vauthors=Sive HL, Hattori K, Weintraub H | title = Progressive determination during formation of the anteroposterior axis in Xenopus laevis | journal = Cell | volume = 58 | issue = 1 | pages = 171–80 |date=July 1989  | pmid = 2752418 | doi = 10.1016/0092-8674(89)90413-3}}</ref> They become expressed in the [[anterior]] region of the [[dorsum (anatomy)|dorsal]] [[ectoderm]] in late [[gastrulation|gastrula embryos]].<ref name="Sive_1989" /><ref name="Sive_1996">{{cite journal |vauthors=Sive H, Bradley L | title = A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning | journal = Dev. Dyn. | volume = 205 | issue = 3 | pages = 265–80 |date=March 1996  | pmid = 8850563 | doi = 10.1002/(SICI)1097-0177(199603)205:3<265::AID-AJA7>3.0.CO;2-G }}</ref>  XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage.<ref name=Aberger>{{cite journal |vauthors=Aberger F, Weidinger G, Grunz H, Richter K | title = Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2 | journal = Mech. Dev. | volume = 72 | issue = 1–2 | pages = 115–30 |date=March 1998  | pmid = 9533957 | doi = 10.1016/S0925-4773(98)00021-5}}</ref>  Many other homologous proteins have been discovered afterwards in Xenopus.
{{PBB_Summary
 
| section_title =  
== Tissue distribution ==
| summary_text =  
 
}}
AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine.<ref name="url_HPA_AGR2">{{cite web | url = http://www.proteinatlas.org/ENSG00000106541/tissue | title = Anterior gradient 2 homolog (Xenopus laevis) | work = Gene/Protein | publisher = The Human Protein Atlas | accessdate = 28 February 2014 }}</ref><ref name="Thompson_1998">{{cite journal |vauthors=Thompson DA, Weigel RJ | title = hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines | journal = Biochem. Biophys. Res. Commun. | volume = 251 | issue = 1 | pages = 111–6 |date=October 1998  | pmid = 9790916 | doi = 10.1006/bbrc.1998.9440 }}</ref> Its protein expression has been shown to be regulated by both androgens and estrogens.<ref name="Bu_2011">{{cite journal |vauthors=Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sültmann H, Cato AC, Klocker H | title = The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection | journal = Prostate | volume = 71 | issue = 6 | pages = 575–87 |date=May 2011  | pmid = 20945500 | doi = 10.1002/pros.21273 | url = }}</ref><ref name="Vanderlaag_2010">{{cite journal |vauthors=Vanderlaag KE, Hudak S, Bald L, Fayadat-Dilman L, Sathe M, Grein J, Janatpour MJ | title = Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin | journal = Breast Cancer Res. | volume = 12 | issue = 3 | pages = R32 | year = 2010 | pmid = 20525379 | pmc = 2917027 | doi = 10.1186/bcr2586 }}</ref>
 
== Structure and function ==
 
AGR2 is a [[protein disulfide isomerase]], with a single CXXS active domain motif for oxidation and reduction reactions.<ref name="humgenomics.com">{{cite journal | vauthors = Galligan JJ, Petersen DR | title = The human protein disulfide isomerase gene family | journal = Human Genomics | volume = 6 | issue = 1 | date = July 2012 | pmid = 23245351 | pmc = 3500226 | doi = 10.1186/1479-7364-6-6 | url = http://www.humgenomics.com/content/6/1/6 }}</ref><ref name="Persson_2005">{{cite journal |vauthors=Persson S, Rosenquist M, Knoblach B, Khosravi-Far R, Sommarin M, Michalak M | title = Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family | journal = Mol. Phylogenet. Evol. | volume = 36 | issue = 3 | pages = 734–40 |date=September 2005  | pmid = 15935701 | doi = 10.1016/j.ympev.2005.04.002 }}</ref> AGR2 forms mixed disulfides in substrates, such as intestinal [[mucin]]. AGR2 interacts with [[MUC2|Mucin 2]] through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2.<ref name="pmid19359471">{{cite journal |vauthors=Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N, Erle DJ | title = The protein disulfide isomerase AGR2 is essential for production of intestinal mucus | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 17 | pages = 6950–5 |date=April 2009  | pmid = 19359471 | pmc = 2678445 | doi = 10.1073/pnas.0808722106 | bibcode = 2009PNAS..106.6950P }}</ref> AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to [[KDEL (amino acid sequence)|KDEL]] and KVEL [[endoplasmic reticulum]] retention sequences.<ref name="pmid22184114">{{cite journal |vauthors=Gupta A, Dong A, Lowe AW | title = AGR2 gene function requires a unique endoplasmic reticulum localization motif | journal = J. Biol. Chem. | volume = 287 | issue = 7 | pages = 4773–82 | year = 2012 | pmid = 22184114 | pmc = 3281655 | doi = 10.1074/jbc.M111.301531 }}</ref>
 
== Clinical significance ==
 
''Agr2'' is located on [[chromosome 7]]p21, a region that has frequent genetic alterations.<ref name="pmid10965104">{{cite journal |vauthors=Petek E, Windpassinger C, Egger H, Kroisel PM, Wagner K | title = Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescencein situ hybridisation | journal = Cytogenet. Cell Genet. | volume = 89 | issue = 3–4 | pages = 141–2 | year = 2000 | pmid = 10965104 | doi = 10.1159/000015594 }}</ref> It was first identified in estrogen receptor-positive breast cancer cells.<ref name="Thompson_1998"/> Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In [[Barrett's esophagus]], ''Agr2'' expression is elevated by over 70 times compared to normal esophageal epithelia.<ref name="pmid16952561">{{cite journal |vauthors=Hao Y, Triadafilopoulos G, Sahbaie P, Young HS, Omary MB, Lowe AW | title = Gene expression profiling reveals stromal genes expressed in common between Barrett's esophagus and adenocarcinoma | journal = Gastroenterology | volume = 131 | issue = 3 | pages = 925–33 |date=September 2006  | pmid = 16952561 | pmc = 2575112 | doi = 10.1053/j.gastro.2006.04.026 }}</ref> Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.<ref name="pmid16569389">{{cite journal |vauthors=Maley CC, Rustgi AK | title = Barrett's esophagus and its progression to adenocarcinoma | journal = J Natl Compr Canc Netw | volume = 4 | issue = 4 | pages = 367–74 |date=April 2006  | pmid = 16569389 | doi = }}</ref>
 
Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate.<ref name=Barraclough>{{cite journal |vauthors=Barraclough DL, Platt-Higgins A, de Silva Rudland S, Barraclough R, Winstanley J, West CR, Rudland PS | title = The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients | journal = Am. J. Pathol. | volume = 175 | issue = 5 | pages = 1848–57 |date=November 2009  | pmid = 19834055 | pmc = 2774050 | doi = 10.2353/ajpath.2009.090246 }}</ref>  AGR2 levels are elevated in the preneoplastic tissue [[Barrett's oesophagus]]. AGR2 is also associated with prostate cancer, though lower levels are associated with higher [[Gleason grade]]s.<ref name="Maresh_2010">{{cite journal |vauthors=Maresh EL, Mah V, Alavi M, Horvath S, Bagryanova L, Liebeskind ES, Knutzen LA, Zhou Y, Chia D, Liu AY, Goodglick L | title = Differential expression of anterior gradient gene AGR2 in prostate cancer | journal = BMC Cancer | volume = 10 | issue = | pages = 680 | year = 2010 | pmid = 21144054 | pmc = 3009682 | doi = 10.1186/1471-2407-10-680 }}</ref>
 
In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with [[inflammatory bowel disease]] and increases in the risk of [[Crohn's disease]] and [[ulcerative colitis]]. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by [[FOXA1]] and [[FOXA2]] molecules (transcription factors for epithelial [[goblet cell]]s) which can activate the AGR2 promoter.<ref name="Zheng_2006">{{cite journal |vauthors=Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nürnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J | title = Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease | journal = Genes Immun. | volume = 7 | issue = 1 | pages = 11–8 |date=January 2006  | pmid = 16222343 | doi = 10.1038/sj.gene.6364263 }}</ref>
 
=== Breast cancer ===
 
In breast cancer, AGR2 and [[Estrogen receptor|estrogen]] (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and [[progesterone receptor]]s (PgR). These patients are normally treated with endocrine therapy. [[Tamoxifen]], which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy,<ref>{{cite web|title=Scientists Unravel Resistance to Breast Cancer Treatment|url=http://www.hopkinsbreastcenter.org/artemis/201212/22.html|publisher=Artemis|accessdate=26 February 2014}}</ref>  and increased AGR2 may be one reason.
 
There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients.<ref name=Hrstka>{{cite journal |vauthors=Hrstka R, Nenutil R, Fourtouna A, Maslon MM, Naughton C, Langdon S, Murray E, Larionov A, Petrakova K, Muller P, Dixon MJ, Hupp TR, Vojtesek B | title = The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers | journal = Oncogene | volume = 29 | issue = 34 | pages = 4838–47 |date=August 2010  | pmid = 20531310 | doi = 10.1038/onc.2010.228 }}</ref><ref name=Innes>{{cite journal |vauthors=Innes HE, Liu D, Barraclough R, Davies MP, O'Neill PA, Platt-Higgins A, de Silva Rudland S, Sibson DR, Rudland PS | title = Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients | journal = Br. J. Cancer | volume = 94 | issue = 7 | pages = 1057–65 |date=April 2006  | pmid = 16598187 | pmc = 2361240 | doi = 10.1038/sj.bjc.6603065 }}</ref> ''Agr2'' mRNA expression is elevated in ''in vitro'' and ''in vivo'' studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen.<ref name=Hrstka /><ref name=Hengel>{{cite journal |vauthors=Hengel SM, Murray E, Langdon S, Hayward L, O'Donoghue J, Panchaud A, Hupp T, Goodlett DR | title = Data-independent proteomic screen identifies novel tamoxifen agonist that mediates drug resistance | journal = J. Proteome Res. | volume = 10 | issue = 10 | pages = 4567–78 |date=October 2011  | pmid = 21936522 | pmc = 3242698 | doi = 10.1021/pr2004117 }}</ref>  Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.<ref name="Hrstka_2013">{{cite journal |vauthors=Hrstka R, Brychtova V, Fabian P, Vojtesek B, Svoboda M | title = AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients | journal = Dis. Markers | volume = 35 | issue = 4 | pages = 207–12 | year = 2013 | pmid = 24167368 | pmc = 3776368 | doi = 10.1155/2013/761537 }}</ref>
Although ''Agr2'' mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the [[anastrozole]] and [[fulvestrant]] has been shown to prevent binding of the ER to the ''Agr2'' promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.<ref name="pmid22853014">{{cite journal |vauthors=Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN | title = Combination anastrozole and fulvestrant in metastatic breast cancer | journal = N. Engl. J. Med. | volume = 367 | issue = 5 | pages = 435–44 | year = 2012 | pmid = 22853014 | pmc = 3951300 | doi = 10.1056/NEJMoa1201622 }}</ref>{{Unreliable medical source|sure=y|date=April 2014}}
 
What AGR2 does in cancers is poorly understood. In breast cancer, [[HSP90]] is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2,<ref name="pmid16175177">{{cite journal |vauthors=Whitesell L, Lindquist SL | title = HSP90 and the chaperoning of cancer | journal = Nat. Rev. Cancer | volume = 5 | issue = 10 | pages = 761–72 | year = 2005 | pmid = 16175177 | doi = 10.1038/nrc1716 }}</ref><ref name="pmid20847343">{{cite journal |vauthors=Simpson NE, Lambert WM, Watkins R, Giashuddin S, Huang SJ, Oxelmark E, Arju R, Hochman T, Goldberg JD, Schneider RJ, Reiz LF, Soares FA, Logan SK, Garabedian MJ | title = High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance | journal = Cancer Res. | volume = 70 | issue = 21 | pages = 8446–56 | year = 2010 | pmid = 20847343 | pmc = 3007122 | doi = 10.1158/0008-5472.CAN-10-1590 }}</ref> so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation,  AGR2 levels peak when milk proteins are produced, and mammary-specific ''Agr2'' knockout mice had downregulated milk protein mRNA expression.<ref name="pmid22819674">{{cite journal |vauthors=Verma S, Salmans ML, Geyfman M, Wang H, Yu Z, Lu Z, Zhao F, Lipkin SM, Andersen B | title = The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development | journal = Dev. Biol. | volume = 369 | issue = 2 | pages = 249–60 | year = 2012 | pmid = 22819674 | pmc = 3465459 | doi = 10.1016/j.ydbio.2012.06.030 }}</ref>
 
===Prostate cancer===
AGR2 is expressed in relatively high levels for [[prostate cancer]] patients. Urine sediment tests determined ''Agr2'' transcript levels to be elevated.<ref name = "Bu_2011" /> AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of ''Agr2'' mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells.<ref name="pmid24587138">{{cite journal |vauthors=Chanda D, Lee JH, Sawant A, Hensel JA, Isayeva T, Reilly SD, Siegal GP, Smith C, Grizzle W, Singh R, Ponnazhagan S | title = Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer | journal = PLoS ONE | volume = 9 | issue = 2 | pages = e89940 | year = 2014 | pmid = 24587138 | pmc = 3937391 | doi = 10.1371/journal.pone.0089940 |bibcode = 2014PLoSO...989940C }}</ref>  AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however.<ref name="Maresh_2010"/> A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.<ref name= "Maresh_2010" />
 
AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation.<ref name="pmid22467239">{{cite journal |vauthors=Hu Z, Gu Y, Han B, Zhang J, Li Z, Tian K, Young CY, Yuan H | title = Knockdown of AGR2 induces cellular senescence in prostate cancer cells | journal = Carcinogenesis | volume = 33 | issue = 6 | pages = 1178–86 | year = 2012 | pmid = 22467239 | doi = 10.1093/carcin/bgs141 }}</ref> AGR2 was determined to be involved in cell adhesion. ''Agr2''-silenced prostate cancer cells had a large decrease in association with [[fibronectin]], lost expression of [[integrin]], and reduced tumor cell migration.<ref name="pmid24587138"/>
 
===Pancreatic cancer===
AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of [[pancreatic tumor]]s and cancer cell lines.<ref name="Ramachandran_2008">{{cite journal |vauthors=Ramachandran V, Arumugam T, Wang H, Logsdon CD | title = Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival | journal = Cancer Res. | volume = 68 | issue = 19 | pages = 7811–8 |date=October 2008  | pmid = 18829536 | doi = 10.1158/0008-5472.CAN-08-1320 | pmc = 4429896 }}</ref> Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of [[gemcitabine]] treatment in pancreatic cancer cell lines ''in vitro'',<ref name= Ramachandran_2008 /><ref name="pmid14695172">{{cite journal |vauthors=Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH | title = Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies | journal = Cancer Res. | volume = 63 | issue = 24 | pages = 8614–22 |date=December 2003  | pmid = 14695172 | doi =  }}</ref>  indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.
 
== Protein interactions ==
 
AGR2 protein has been demonstrated to interact with [[LYPD3|C4.4A]] and [[Dystroglycan|DAG-1]] proteins which are associated with [[metastasis]] formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells.<ref name="Fletcher_2003">{{cite journal |vauthors=Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA, Daviet L, Legrain P, Parekh R, Harris AL, Terrett JA | title = hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan | journal = Br. J. Cancer | volume = 88 | issue = 4 | pages = 579–85 |date=February 2003  | pmid = 12592373 | pmc = 2377166 | doi = 10.1038/sj.bjc.6600740 }}</ref> AGR2 is able to suppress [[p53]] activity by preventing [[phosphorylation]] after [[DNA damage]].<ref name=pmid14967811 /> AGR2 has been shown to bind to [[Reptin]], a tumor repressor, in the nucleus.<ref name="pmid20888340">{{cite journal |vauthors=Maslon MM, Hrstka R, Vojtesek B, Hupp TR | title = A divergent substrate-binding loop within the pro-oncogenic protein anterior gradient-2 forms a docking site for Reptin | journal = J. Mol. Biol. | volume = 404 | issue = 3 | pages = 418–38 | year = 2010 | pmid = 20888340 | doi = 10.1016/j.jmb.2010.09.035 }}</ref>
 
{{clear}}


==References==
==References==
{{reflist|2}}
{{reflist|35em}}
 
==External links==
* {{UCSC gene info|AGR2}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin|35em}}
{{PBB_Further_reading
*{{cite journal  |vauthors=Zhang JS, Gong A, Cheville JC, Smith DI, Young CY |title=AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer |journal=Genes Chromosomes Cancer |volume=43 |issue= 3 |pages= 249–59 |year= 2005 |pmid= 15834940 |doi= 10.1002/gcc.20188 }}
| citations =
*{{cite journal  |vauthors=Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, Winzer KJ, Dietel M, Kristiansen G |title=Prognostic relevance of AGR2 expression in breast cancer |journal=Clin. Cancer Res. |volume=12 |issue= 6 |pages= 1728–34 |year= 2006 |pmid= 16551856 |doi= 10.1158/1078-0432.CCR-05-2057 }}
*{{cite journal  | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171-4 |year= 1994 |pmid= 8125298 |doi=  }}
*{{cite journal  |vauthors=Zhang Y, Forootan SS, Liu D, Barraclough R, Foster CS, Rudland PS, Ke Y |title=Increased expression of anterior gradient-2 is significantly associated with poor survival of prostate cancer patients |journal=Prostate Cancer Prostatic Dis. |volume=10 |issue= 3 |pages= 293–300 |year= 2007 |pmid= 17457305 |doi= 10.1038/sj.pcan.4500960 }}
*{{cite journal  | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, ''et al.'' |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149-56 |year= 1997 |pmid= 9373149 |doi=  }}
*{{cite journal  | author=Thompson DA, Weigel RJ |title=hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines. |journal=Biochem. Biophys. Res. Commun. |volume=251 |issue= 1 |pages= 111-6 |year= 1998 |pmid= 9790916 |doi= 10.1006/bbrc.1998.9440 }}
*{{cite journal  | author=Petek E, Windpassinger C, Egger H, ''et al.'' |title=Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescencein situ hybridisation. |journal=Cytogenet. Cell Genet. |volume=89 |issue= 3-4 |pages= 141-2 |year= 2000 |pmid= 10965104 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
*{{cite journal  | author=Fletcher GC, Patel S, Tyson K, ''et al.'' |title=hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan. |journal=Br. J. Cancer |volume=88 |issue= 4 |pages= 579-85 |year= 2003 |pmid= 12592373 |doi= 10.1038/sj.bjc.6600740 }}
*{{cite journal  | author=Scherer SW, Cheung J, MacDonald JR, ''et al.'' |title=Human chromosome 7: DNA sequence and biology. |journal=Science |volume=300 |issue= 5620 |pages= 767-72 |year= 2003 |pmid= 12690205 |doi= 10.1126/science.1083423 }}
*{{cite journal  | author=Hillier LW, Fulton RS, Fulton LA, ''et al.'' |title=The DNA sequence of human chromosome 7. |journal=Nature |volume=424 |issue= 6945 |pages= 157-64 |year= 2003 |pmid= 12853948 |doi= 10.1038/nature01782 }}
*{{cite journal  | author=Clark HF, Gurney AL, Abaya E, ''et al.'' |title=The secreted protein discovery initiative (SPDI), a large-scale effort to identify novel human secreted and transmembrane proteins: a bioinformatics assessment. |journal=Genome Res. |volume=13 |issue= 10 |pages= 2265-70 |year= 2003 |pmid= 12975309 |doi= 10.1101/gr.1293003 }}
*{{cite journal  | author=Zhang Z, Henzel WJ |title=Signal peptide prediction based on analysis of experimentally verified cleavage sites. |journal=Protein Sci. |volume=13 |issue= 10 |pages= 2819-24 |year= 2005 |pmid= 15340161 |doi= 10.1110/ps.04682504 }}
*{{cite journal  | author=Gerhard DS, Wagner L, Feingold EA, ''et al.'' |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121-7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504 }}
*{{cite journal  | author=Zhang JS, Gong A, Cheville JC, ''et al.'' |title=AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer. |journal=Genes Chromosomes Cancer |volume=43 |issue= 3 |pages= 249-59 |year= 2005 |pmid= 15834940 |doi= 10.1002/gcc.20188 }}
*{{cite journal  | author=Persson S, Rosenquist M, Knoblach B, ''et al.'' |title=Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. |journal=Mol. Phylogenet. Evol. |volume=36 |issue= 3 |pages= 734-40 |year= 2005 |pmid= 15935701 |doi= 10.1016/j.ympev.2005.04.002 }}
*{{cite journal  | author=Stelzl U, Worm U, Lalowski M, ''et al.'' |title=A human protein-protein interaction network: a resource for annotating the proteome. |journal=Cell |volume=122 |issue= 6 |pages= 957-68 |year= 2005 |pmid= 16169070 |doi= 10.1016/j.cell.2005.08.029 }}
*{{cite journal  | author=Rual JF, Venkatesan K, Hao T, ''et al.'' |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173-8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209 }}
*{{cite journal  | author=Fritzsche FR, Dahl E, Pahl S, ''et al.'' |title=Prognostic relevance of AGR2 expression in breast cancer. |journal=Clin. Cancer Res. |volume=12 |issue= 6 |pages= 1728-34 |year= 2006 |pmid= 16551856 |doi= 10.1158/1078-0432.CCR-05-2057 }}
*{{cite journal  | author=Lim J, Hao T, Shaw C, ''et al.'' |title=A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. |journal=Cell |volume=125 |issue= 4 |pages= 801-14 |year= 2006 |pmid= 16713569 |doi= 10.1016/j.cell.2006.03.032 }}
*{{cite journal  | author=Zhang Y, Forootan SS, Liu D, ''et al.'' |title=Increased expression of anterior gradient-2 is significantly associated with poor survival of prostate cancer patients. |journal=Prostate Cancer Prostatic Dis. |volume=10 |issue= 3 |pages= 293-300 |year= 2007 |pmid= 17457305 |doi= 10.1038/sj.pcan.4500960 }}
}}
{{refend}}
{{refend}}


{{protein-stub}}
[[Category:Endoplasmic reticulum resident proteins]]
{{WikiDoc Sources}}

Latest revision as of 15:55, 18 October 2018

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Identifiers
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External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
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Anterior gradient protein 2 homolog (AGR-2), also known as secreted cement gland protein XAG-2 homolog, is a protein that in humans is encoded by the AGR2 gene. Anterior gradient homolog 2 was originally discovered in Xenopus laevis.[1] In Xenopus AGR2 plays a role in cement gland differentiation,[2] but in human cancer cell lines high levels of AGR2 correlate with downregulation of the p53 response,[3] cell migration, and cell transformation.[4] However, there have been other observations that AGR2 can repress growth and proliferation.[5]

Discovery in Xenopus laevis

The Xenopus laevis anterior gradient genes - XAG-1, XAG-2, and XAG-3 - were discovered through dissection of different-aged embryos.[6] They become expressed in the anterior region of the dorsal ectoderm in late gastrula embryos.[6][7] XAG-2 expression gathers at the anterior region of the dorsal ectoderm, and this region corresponds to the cement gland anlage.[8] Many other homologous proteins have been discovered afterwards in Xenopus.

Tissue distribution

AGR2 is the human homolog of XAG-2. It is expressed strongly in tissues that secrete mucus or function as endocrine organs, including the lungs, stomach, colon, prostate and small intestine.[9][10] Its protein expression has been shown to be regulated by both androgens and estrogens.[5][11]

Structure and function

AGR2 is a protein disulfide isomerase, with a single CXXS active domain motif for oxidation and reduction reactions.[12][13] AGR2 forms mixed disulfides in substrates, such as intestinal mucin. AGR2 interacts with Mucin 2 through its thioredoxin-like domain forming a heterodisulfide bond with cysteine residues in MUC2.[14] AGR2 is suggested to play a role in protein folding, and it has a KTEL C-terminal motif similar to KDEL and KVEL endoplasmic reticulum retention sequences.[15]

Clinical significance

Agr2 is located on chromosome 7p21, a region that has frequent genetic alterations.[16] It was first identified in estrogen receptor-positive breast cancer cells.[10] Later studies showed elevated levels of AGR2 in adenocarcinomas of the esophagus, pancreas, and prostate. In Barrett's esophagus, Agr2 expression is elevated by over 70 times compared to normal esophageal epithelia.[17] Thus, this protein alone is enough to distinguish Barrett's esophagus, which is linked to esophageal adenocarcinoma, from a normal esophagus.[18]

Varying AGR2 levels exist in different cancers. In breast cancer, high AGR2 expression is correlated with low survival rate.[19] AGR2 levels are elevated in the preneoplastic tissue Barrett's oesophagus. AGR2 is also associated with prostate cancer, though lower levels are associated with higher Gleason grades.[20]

In contrast to upregulation of AGR2 in various cancers, downregulation of AGR2 is linked with inflammatory bowel disease and increases in the risk of Crohn's disease and ulcerative colitis. This implies the importance of AGR2 in maintaining epithelial barrier function, which is supported by FOXA1 and FOXA2 molecules (transcription factors for epithelial goblet cells) which can activate the AGR2 promoter.[21]

Breast cancer

In breast cancer, AGR2 and estrogen (ER) expression are positively correlated. Approximately 70% of breast cancer patients have breast cancer cells that heavily express ER and progesterone receptors (PgR). These patients are normally treated with endocrine therapy. Tamoxifen, which blocks the binding of estradiol to its receptor, is the standard treatment for ER-positive breast cancer. However, about one third of patients do not respond to this therapy,[22] and increased AGR2 may be one reason.

There is a positive correlation for a higher level of AGR2 expression with poor therapeutic results in ERα-positive breast cancer patients.[23][24] Agr2 mRNA expression is elevated in in vitro and in vivo studies responding to tamoxifen adjuvant therapy, so AGR2 is likely provides an agonistic effect on tamoxifen.[23][25] Therefore, AGR2 is a possible predictive biomarker when selecting patients with ER-positive breast cancer to participate this therapy.[26] Although Agr2 mRNA levels are correlated with the tamoxifen therapy response, AGR2 protein levels have yet to be statistically associated with the therapy. A combinatorial therapy using the anastrozole and fulvestrant has been shown to prevent binding of the ER to the Agr2 promoter, and there has been improved prognosis in the patients receiving it, possibly because AGR2 expression in the tumors have been reduced.[27][unreliable medical source]

What AGR2 does in cancers is poorly understood. In breast cancer, HSP90 is a molecular chaperone expressed in tumor cells when there exists an excess of unfolded protein, and its co-chaperone has been reported to induce expression of AGR2,[28][29] so AGR2 may be used by the endoplasmic reticulum to assist with protein folding to alleviate proteotoxic stress. AGR2 may help regulate the protein and mRNA levels in a cell overall as well. During late pregnancy and lactation, AGR2 levels peak when milk proteins are produced, and mammary-specific Agr2 knockout mice had downregulated milk protein mRNA expression.[30]

Prostate cancer

AGR2 is expressed in relatively high levels for prostate cancer patients. Urine sediment tests determined Agr2 transcript levels to be elevated.[5] AGR2 expression was increased in metastatic prostate cancer cells cultured in a bone marrow microenvironment, where intense levels of Agr2 mRNA were detected, suggesting AGR2 is required for bone metastasis of prostate cancer cells.[31] AGR2 transcript levels were lower in metastatic lesions compared to the primary tumor, however.[20] A greater chance of prostate cancer recurrence is linked to relatively lower levels of AGR2.[20]

AGR2 depletion through gene knockdown was shown to result in accumulation of prostate cancer cell lines at the G0/G1 phase of the cell cycle, while forced expression of AGR led to an increase in cell proliferation.[32] AGR2 was determined to be involved in cell adhesion. Agr2-silenced prostate cancer cells had a large decrease in association with fibronectin, lost expression of integrin, and reduced tumor cell migration.[31]

Pancreatic cancer

AGR2 mRNA was discovered to be increased in precancerous lesions and neoplastic cells of pancreatic tumors and cancer cell lines.[33] Transient silencing of AGR2 by small interfering RNA and short hairpin RNA significantly reduces cell proliferation and invasion while increasing the effectiveness of gemcitabine treatment in pancreatic cancer cell lines in vitro,[33][34] indicating that AGR2 can help pancreatic cancer cells survive and protect tumors from chemotherapeutic treatments for pancreatic cancer. This is critical because pancreatic cancer is well recognized as being highly resistant to therapeutics, and five-year survival rates for pancreatic cancer are extremely low.

Protein interactions

AGR2 protein has been demonstrated to interact with C4.4A and DAG-1 proteins which are associated with metastasis formation since these transmembrane proteins are involved in cell and matrix interactions between cancer and normal cells.[35] AGR2 is able to suppress p53 activity by preventing phosphorylation after DNA damage.[3] AGR2 has been shown to bind to Reptin, a tumor repressor, in the nucleus.[36]

References

  1. ↑ "Entrez Gene: AGR2 anterior gradient homolog 2 (Xenopus laevis)".
  2. ↑ Aberger F, Weidinger G, Grunz H, Richter K (March 1998). "Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2". Mech. Dev. 72 (1–2): 115–30. doi:10.1016/S0925-4773(98)00021-5. PMID 9533957.
  3. ↑ 3.0 3.1 Pohler E, Craig AL, Cotton J, Lawrie L, Dillon JF, Ross P, Kernohan N, Hupp TR (June 2004). "The Barrett's antigen anterior gradient-2 silences the p53 transcriptional response to DNA damage". Mol. Cell. Proteomics. 3 (6): 534–47. doi:10.1074/mcp.M300089-MCP200. PMID 14967811.
  4. ↑ Wang Z, Hao Y, Lowe AW (January 2008). "The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation". Cancer Res. 68 (2): 492–7. doi:10.1158/0008-5472.CAN-07-2930. PMID 18199544.
  5. ↑ 5.0 5.1 5.2 Bu H, Bormann S, Schäfer G, Horninger W, Massoner P, Neeb A, Lakshmanan VK, Maddalo D, Nestl A, Sültmann H, Cato AC, Klocker H (May 2011). "The anterior gradient 2 (AGR2) gene is overexpressed in prostate cancer and may be useful as a urine sediment marker for prostate cancer detection". Prostate. 71 (6): 575–87. doi:10.1002/pros.21273. PMID 20945500.
  6. ↑ 6.0 6.1 Sive HL, Hattori K, Weintraub H (July 1989). "Progressive determination during formation of the anteroposterior axis in Xenopus laevis". Cell. 58 (1): 171–80. doi:10.1016/0092-8674(89)90413-3. PMID 2752418.
  7. ↑ Sive H, Bradley L (March 1996). "A sticky problem: the Xenopus cement gland as a paradigm for anteroposterior patterning". Dev. Dyn. 205 (3): 265–80. doi:10.1002/(SICI)1097-0177(199603)205:3<265::AID-AJA7>3.0.CO;2-G. PMID 8850563.
  8. ↑ Aberger F, Weidinger G, Grunz H, Richter K (March 1998). "Anterior specification of embryonic ectoderm: the role of the Xenopus cement gland-specific gene XAG-2". Mech. Dev. 72 (1–2): 115–30. doi:10.1016/S0925-4773(98)00021-5. PMID 9533957.
  9. ↑ "Anterior gradient 2 homolog (Xenopus laevis)". Gene/Protein. The Human Protein Atlas. Retrieved 28 February 2014.
  10. ↑ 10.0 10.1 Thompson DA, Weigel RJ (October 1998). "hAG-2, the human homologue of the Xenopus laevis cement gland gene XAG-2, is coexpressed with estrogen receptor in breast cancer cell lines". Biochem. Biophys. Res. Commun. 251 (1): 111–6. doi:10.1006/bbrc.1998.9440. PMID 9790916.
  11. ↑ Vanderlaag KE, Hudak S, Bald L, Fayadat-Dilman L, Sathe M, Grein J, Janatpour MJ (2010). "Anterior gradient-2 plays a critical role in breast cancer cell growth and survival by modulating cyclin D1, estrogen receptor-alpha and survivin". Breast Cancer Res. 12 (3): R32. doi:10.1186/bcr2586. PMC 2917027. PMID 20525379.
  12. ↑ Galligan JJ, Petersen DR (July 2012). "The human protein disulfide isomerase gene family". Human Genomics. 6 (1). doi:10.1186/1479-7364-6-6. PMC 3500226. PMID 23245351.
  13. ↑ Persson S, Rosenquist M, Knoblach B, Khosravi-Far R, Sommarin M, Michalak M (September 2005). "Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family". Mol. Phylogenet. Evol. 36 (3): 734–40. doi:10.1016/j.ympev.2005.04.002. PMID 15935701.
  14. ↑ Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N, Erle DJ (April 2009). "The protein disulfide isomerase AGR2 is essential for production of intestinal mucus". Proc. Natl. Acad. Sci. U.S.A. 106 (17): 6950–5. Bibcode:2009PNAS..106.6950P. doi:10.1073/pnas.0808722106. PMC 2678445. PMID 19359471.
  15. ↑ Gupta A, Dong A, Lowe AW (2012). "AGR2 gene function requires a unique endoplasmic reticulum localization motif". J. Biol. Chem. 287 (7): 4773–82. doi:10.1074/jbc.M111.301531. PMC 3281655. PMID 22184114.
  16. ↑ Petek E, Windpassinger C, Egger H, Kroisel PM, Wagner K (2000). "Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescencein situ hybridisation". Cytogenet. Cell Genet. 89 (3–4): 141–2. doi:10.1159/000015594. PMID 10965104.
  17. ↑ Hao Y, Triadafilopoulos G, Sahbaie P, Young HS, Omary MB, Lowe AW (September 2006). "Gene expression profiling reveals stromal genes expressed in common between Barrett's esophagus and adenocarcinoma". Gastroenterology. 131 (3): 925–33. doi:10.1053/j.gastro.2006.04.026. PMC 2575112. PMID 16952561.
  18. ↑ Maley CC, Rustgi AK (April 2006). "Barrett's esophagus and its progression to adenocarcinoma". J Natl Compr Canc Netw. 4 (4): 367–74. PMID 16569389.
  19. ↑ Barraclough DL, Platt-Higgins A, de Silva Rudland S, Barraclough R, Winstanley J, West CR, Rudland PS (November 2009). "The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients". Am. J. Pathol. 175 (5): 1848–57. doi:10.2353/ajpath.2009.090246. PMC 2774050. PMID 19834055.
  20. ↑ 20.0 20.1 20.2 Maresh EL, Mah V, Alavi M, Horvath S, Bagryanova L, Liebeskind ES, Knutzen LA, Zhou Y, Chia D, Liu AY, Goodglick L (2010). "Differential expression of anterior gradient gene AGR2 in prostate cancer". BMC Cancer. 10: 680. doi:10.1186/1471-2407-10-680. PMC 3009682. PMID 21144054.
  21. ↑ Zheng W, Rosenstiel P, Huse K, Sina C, Valentonyte R, Mah N, Zeitlmann L, Grosse J, Ruf N, Nürnberg P, Costello CM, Onnie C, Mathew C, Platzer M, Schreiber S, Hampe J (January 2006). "Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease". Genes Immun. 7 (1): 11–8. doi:10.1038/sj.gene.6364263. PMID 16222343.
  22. ↑ "Scientists Unravel Resistance to Breast Cancer Treatment". Artemis. Retrieved 26 February 2014.
  23. ↑ 23.0 23.1 Hrstka R, Nenutil R, Fourtouna A, Maslon MM, Naughton C, Langdon S, Murray E, Larionov A, Petrakova K, Muller P, Dixon MJ, Hupp TR, Vojtesek B (August 2010). "The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers". Oncogene. 29 (34): 4838–47. doi:10.1038/onc.2010.228. PMID 20531310.
  24. ↑ Innes HE, Liu D, Barraclough R, Davies MP, O'Neill PA, Platt-Higgins A, de Silva Rudland S, Sibson DR, Rudland PS (April 2006). "Significance of the metastasis-inducing protein AGR2 for outcome in hormonally treated breast cancer patients". Br. J. Cancer. 94 (7): 1057–65. doi:10.1038/sj.bjc.6603065. PMC 2361240. PMID 16598187.
  25. ↑ Hengel SM, Murray E, Langdon S, Hayward L, O'Donoghue J, Panchaud A, Hupp T, Goodlett DR (October 2011). "Data-independent proteomic screen identifies novel tamoxifen agonist that mediates drug resistance". J. Proteome Res. 10 (10): 4567–78. doi:10.1021/pr2004117. PMC 3242698. PMID 21936522.
  26. ↑ Hrstka R, Brychtova V, Fabian P, Vojtesek B, Svoboda M (2013). "AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients". Dis. Markers. 35 (4): 207–12. doi:10.1155/2013/761537. PMC 3776368. PMID 24167368.
  27. ↑ Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN (2012). "Combination anastrozole and fulvestrant in metastatic breast cancer". N. Engl. J. Med. 367 (5): 435–44. doi:10.1056/NEJMoa1201622. PMC 3951300. PMID 22853014.
  28. ↑ Whitesell L, Lindquist SL (2005). "HSP90 and the chaperoning of cancer". Nat. Rev. Cancer. 5 (10): 761–72. doi:10.1038/nrc1716. PMID 16175177.
  29. ↑ Simpson NE, Lambert WM, Watkins R, Giashuddin S, Huang SJ, Oxelmark E, Arju R, Hochman T, Goldberg JD, Schneider RJ, Reiz LF, Soares FA, Logan SK, Garabedian MJ (2010). "High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance". Cancer Res. 70 (21): 8446–56. doi:10.1158/0008-5472.CAN-10-1590. PMC 3007122. PMID 20847343.
  30. ↑ Verma S, Salmans ML, Geyfman M, Wang H, Yu Z, Lu Z, Zhao F, Lipkin SM, Andersen B (2012). "The estrogen-responsive Agr2 gene regulates mammary epithelial proliferation and facilitates lobuloalveolar development". Dev. Biol. 369 (2): 249–60. doi:10.1016/j.ydbio.2012.06.030. PMC 3465459. PMID 22819674.
  31. ↑ 31.0 31.1 Chanda D, Lee JH, Sawant A, Hensel JA, Isayeva T, Reilly SD, Siegal GP, Smith C, Grizzle W, Singh R, Ponnazhagan S (2014). "Anterior gradient protein-2 is a regulator of cellular adhesion in prostate cancer". PLoS ONE. 9 (2): e89940. Bibcode:2014PLoSO...989940C. doi:10.1371/journal.pone.0089940. PMC 3937391. PMID 24587138.
  32. ↑ Hu Z, Gu Y, Han B, Zhang J, Li Z, Tian K, Young CY, Yuan H (2012). "Knockdown of AGR2 induces cellular senescence in prostate cancer cells". Carcinogenesis. 33 (6): 1178–86. doi:10.1093/carcin/bgs141. PMID 22467239.
  33. ↑ 33.0 33.1 Ramachandran V, Arumugam T, Wang H, Logsdon CD (October 2008). "Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival". Cancer Res. 68 (19): 7811–8. doi:10.1158/0008-5472.CAN-08-1320. PMC 4429896. PMID 18829536.
  34. ↑ Iacobuzio-Donahue CA, Ashfaq R, Maitra A, Adsay NV, Shen-Ong GL, Berg K, Hollingsworth MA, Cameron JL, Yeo CJ, Kern SE, Goggins M, Hruban RH (December 2003). "Highly expressed genes in pancreatic ductal adenocarcinomas: a comprehensive characterization and comparison of the transcription profiles obtained from three major technologies". Cancer Res. 63 (24): 8614–22. PMID 14695172.
  35. ↑ Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA, Daviet L, Legrain P, Parekh R, Harris AL, Terrett JA (February 2003). "hAG-2 and hAG-3, human homologues of genes involved in differentiation, are associated with oestrogen receptor-positive breast tumours and interact with metastasis gene C4.4a and dystroglycan". Br. J. Cancer. 88 (4): 579–85. doi:10.1038/sj.bjc.6600740. PMC 2377166. PMID 12592373.
  36. ↑ Maslon MM, Hrstka R, Vojtesek B, Hupp TR (2010). "A divergent substrate-binding loop within the pro-oncogenic protein anterior gradient-2 forms a docking site for Reptin". J. Mol. Biol. 404 (3): 418–38. doi:10.1016/j.jmb.2010.09.035. PMID 20888340.

External links

Further reading

  • Zhang JS, Gong A, Cheville JC, Smith DI, Young CY (2005). "AGR2, an androgen-inducible secretory protein overexpressed in prostate cancer". Genes Chromosomes Cancer. 43 (3): 249–59. doi:10.1002/gcc.20188. PMID 15834940.
  • Fritzsche FR, Dahl E, Pahl S, Burkhardt M, Luo J, Mayordomo E, Gansukh T, Dankof A, Knuechel R, Denkert C, Winzer KJ, Dietel M, Kristiansen G (2006). "Prognostic relevance of AGR2 expression in breast cancer". Clin. Cancer Res. 12 (6): 1728–34. doi:10.1158/1078-0432.CCR-05-2057. PMID 16551856.
  • Zhang Y, Forootan SS, Liu D, Barraclough R, Foster CS, Rudland PS, Ke Y (2007). "Increased expression of anterior gradient-2 is significantly associated with poor survival of prostate cancer patients". Prostate Cancer Prostatic Dis. 10 (3): 293–300. doi:10.1038/sj.pcan.4500960. PMID 17457305.
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