Abstract
Introduction: Basal-like Breast Cancer (BLBC) represents an important molecular subtype of breast
cancer characterized by an aggressive behavior, molecular pathology poorly understood
and a limited treatment. Objective: We aim to search for molecular differences between non-BLBC and BLBC tumors in order
to propose possible diagnostic and prognostic biomarkers using databases. Metodology: Microarray processed data were downloaded from GEO database considering non-BLBC
and BLBC. Enrichment analysis was evaluated using GO consortium and Ingenuity, protein–protein
interaction, gene Ontology and co-expression analysis using STRING. Gene expression
data was extracted using TCGA, METABRIC and Breast Cancer Gene-Expression Miner v4.2
databases. The Survival was evaluated using The Kaplan–Meier plotter. Results: Were identified 58 upregulated and 58 downregulated genes enriched in signaling pathways
like PDGF, Angiogenesis, Integrin and WNT. AGR2 and AGR3 expression were reduced in
BLBC in relation to non-BLBC tumors, patients aged ≤51 years, and with negativity
of ER, PR and HER-2 and nodal status. Low expression of AGR2 and AGR3 were associated
with worse OS and RFS for all breast cancer cases. But according to the molecular
stratification, low AGR2 conferred worst OS in luminal A, worst RFS in BLBC and good
OS and RFS in luminal B. High AGR3 conferred worse OS and RFS in BLBC, but low AGR3
attributed worse OS in luminal A. Conclusion: AGR2 and AGR3 expression were able to differentiate non-BLBC from BLBC. Downregulation
of AGR2 and AGR3 was associated with BLBC clinical phenotype. Furthermore, both genes
behave different when considering prognosis and molecular stratification.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Clinical Breast CancerAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
Reference
- Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin [Internet]. 2018; 68 (Available at:): 394-424
Perou CM, Sùrlie T, Eisen MB, et al. <Molecular-Portraits-Breast-Cancer_Perou-Botstein_Nature-p747_2000_REF_5.pdf>. 2000;533:747–52.
- Repeated observation of breast tumor subtypes in independent gene expression data sets.Proc Natl Acad Sci [Internet]. 2003; 100 (Available at:): 8418-8423
- Immunohistochemical and Clinical Characterization of the Basal- Like Subtype of Invasive Breast Carcinoma.Clin Cancer Res. 2004; 10: 5367-5374
- The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer.Int J Mol Sci. 2019; 20: 1-30
- The role of taxanes in triple-negative breast cancer: Literature review.Drug Des Devel Ther. 2015; 5: 4303-4318
- Triple-negative breast cancer: Clinical features and patterns of recurrence.Clin Cancer Res. 2007; 13: 4429-4434
- Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR.Am J Surg Pathol. 2006; 30: 1097-1104
- Expression of luminal and basal cytokeratins in human breast carcinoma.J Pathol. 2004; 203: 661-671
- X chromosomal abnormalities in basal-like human breast cancer.Cancer Cell. 2006; 9: 121-132
- Subtle variations in Pten dose determine cancer susceptibility.Nat Genet. 2010; 42: 454-458
- PANTHER version 11: Expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements.Nucleic Acids Res. 2017; 4: D183-D189
- STITCH: Interaction networks of chemicals and proteins.Nucleic Acids Res. 2008; 36 ((Databas:): D684-D688
- STITCH 5: Augmenting protein-chemical interaction networks with tissue and affinity data.Nucleic Acids Res. 2016; 4: D380-D384
- The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.Cancer Discov [Internet]. 2012; 2 (Available at:): 401-404
- Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal Jianjiong.Sci Signal. 2013; 6: 1-34
- Protein tyrosine phosphatase UBASH3B is overexpressed in triple-negative breast cancer and promotes invasion and metastasis.Proc Natl Acad Sci U S A. 2013; 110: 11121-11126
- Bc-GenExMiner: An easy-to-use online platform for gene prognostic analyses in breast cancer.Breast Cancer Res Treat. 2012; 131: 765-775
- bc-GenExMiner 3.0: New mining module computes breast cancer gene expression correlation analyses.Database. 2013; 2013: 1-9
- An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients.Breast Cancer Res Treat. 2010; 123: 725-731
- Clinical utility of fulvestrant in the treatment of breast cancer: A report on the emerging clinical evidence.Cancer Manag Res. 2018; 30: 3083-3099
- Targeted therapeutic options and future perspectives for HER2-positive breast cancer.Signal Transduct Target Ther [Internet]. 2019; 4 (doi:)https://doi.org/10.1038/s41392-019-0069-2
- Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling.Nat Med. 2018; 24: 463-473
- Absence of integrin α3β1 promotes the progression of HER2-driven breast cancer in vivo.Breast Cancer Res. 2019; 17: 1-17
- WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling.Cell Commun Signal. 2019; 17: 1-19
- FOXA1 represses the molecular phenotype of basal breast cancer cells.Oncogene. 2013; 32: 554-563
- Triggering a switch from basal- to luminal-like breast cancer subtype by the small-molecule diptoindonesin G via induction of GABARAPL1.Cell Death Dis. 2020; 11: 1-13
- Robust identification of target genes and outliers in triple-negative breast cancer data.Stat Methods Med Res. 2018; 28: 3042-3056
- Evaluation of AGR2 and AGR3 as candidate genes for inflammatory bowel disease.Genes Immun [Internet]. 2006; 7 (Available at:): 11-18
- The protein disulfide isomerase family: Key players in health and disease.Antioxidants Redox Signal. 2012; 15: 781-789
- Localization of the human anterior gradient-2 gene (AGR2) to chromosome band 7p21.3 by radiation hybrid mapping and fluorescence in situ hybridisation.Cytogenet Cell Genet. 2000; 89: 141-142
- 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. 2003; 88: 579-585
- The adenocarcinoma-associated antigen, AGR2, promotes tumor growth, cell migration, and cellular transformation.Cancer Res. 2008; 68: 492-497
- AGR2 oncoprotein inhibits p38 MAPK and p53 activation through a DUSP10-mediated regulatory pathway.Mol Oncol [Internet]. 2016; 10 (Available at:): 652-662https://doi.org/10.1016/j.molonc.2015.12.003
- Extracellular AGR3 regulates breast cancer cells migration via Src signaling.Oncol Lett. 2019; 18: 4449-4456
- The protein disulfide isomerase AGR2 is essential for production of intestinal mucus.PNAS. 2009; 106: 6950-6955
- Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice.Dev Biol. 2010; 15: 270-279
- ER stress protein AGR2 precedes and is involved in the regulation of pancreatic cancer initiation.Oncogene. 2017; 36: 3094-3103
- AGR2 diagnostic value in nasopharyngeal carcinoma prognosis.Clin Chim Acta [Internet]. 2018; 484 (doi:): 323-327https://doi.org/10.1016/j.cca.2017.12.023
- Anterior gradient 2 overexpression in lung adenocarcinoma.Appl Immunohistochem Mol Morphol. 2012; 20: 31-36
- 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. 2011; 71: 575-587
- AGR2, a mucinous ovarian cancer marker, promotes cell proliferation and migration.Exp Mol Med. 2011; 43: 91-100
- AGR3 in breast cancer: Prognostic impact and suitable serum-based biomarker for early cancer detection.PLoS One. 2015; 10: 1-18
- Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling.Exp Cell Res. 2018; 15: 198-207
- Anterior gradient 2 is expressed and secreted during the development of pancreatic cancer and promotes cancer cell survival.Cancer Res. 2008; 1: 7811-7818
- MiR-135b-5p enhances doxorubicin-sensitivity of breast cancer cells through targeting anterior gradient 2.J Exp Clin Cancer Res. 2019; 38: 1-13
- Anterior Gradient-3: A novel biomarker for ovarian cancer that mediates cisplatin resistance in xenograft models.J Immunol Methods [Internet]. 2012; 378 (doi:): 20-32https://doi.org/10.1016/j.jim.2012.01.013
- The anterior gradient homolog 3 (AGR3) gene is associated with differentiation and survival in ovarian cancer.Am J Surg Pathol. 2011; 35: 904-912
- Differential expression of anterior gradient protein 3 in intrahepatic cholangiocarcinoma and hepatocellular carcinoma.Exp Mol Pathol [Internet]. 2014; 96 (doi:): 375-381https://doi.org/10.1016/j.yexmp.2014.04.002
- Anterior gradient 2 and 3 - Two prototype androgen-responsive genes transcriptionally upregulated by androgens and by oestrogens in prostate cancer cells.FEBS J. 2013; 280: 1249-1266
- AGR3 promotes the stemness of colorectal cancer via modulating Wnt/β-catenin signalling.Cell Signal. 2020; 65: 1-25
- Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response.Cancer Research and Treatment. 2019; (p.): 1-52
- Identification and prognostic value of anterior gradient protein 2 expression in breast cancer based on tissue microarray.Tumor Biol. 2017; 39: 1-9
- The estrogen-regulated anterior gradient 2 (AGR2) protein in breast cancer: a potential drug target and biomarker.Breast Cancer Res [Internet]. 2013; 15 (Available at:): 204
- Anterior Gradient 2 is a Poor Outcome Indicator in Luminal Breast Cancer.Ann Surg Oncol. 2015; 22: 3489-3496
- 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. 1998; 251: 111-116
- Prognostic relevance of AGR2 expression in breast cancer.Clin Cancer Res. 2006; 12: 1728-1734
- The metastasis-associated anterior gradient 2 protein is correlated with poor survival of breast cancer patients.Am J Pathol [Internet]. 2009; 175 (doi:): 1848-1857https://doi.org/10.2353/ajpath.2009.090246
- Human homologue of cement gland protein, a novel metastasis inducer associated with breast carcinomas.Cancer Res. 2005; 1: 3796-3805
- Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients.Onco Targets Ther. 2015; 8: 1523-1532
- The prognostic value of AGR2 expression in solid tumours: A systematic review and meta-analysis.Sci Rep. 2017; 7: 1-10
- High expression of AGR2 in lung cancer is predictive of poor survival.BMC Cancer. 2015; 6: 1-9
- Downregulation of AGR2, p21, and cyclin D and alterations in p53 function were associated with tumor progression and chemotherapy resistance in epithelial ovarian carcinoma.Cancer Med. 2018; 29: 1-12
- Loss of Anterior Gradient-2 expression is an independent prognostic factor in colorectal carcinomas.Eur J Cancer [Internet]. 2014; (doi:)https://doi.org/10.1016/j.ejca.2014.04.012
- AGR2 predicts tamoxifen resistance in postmenopausal breast cancer patients.Dis Markers. 2013; 35: 207-212
- A gene-expression signature as a predictor of survival in breast cancer.N Engl J Med. 2002; 347: 1999-2009
- Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer.Breast Cancer Res. 2010; 12: 1-18
- A refined molecular taxonomy of breast cancer.Oncogene. 2012; 1: 1196-1206
- Characterisation of tumoral markers correlated with ErbB2 (HER2/Neu) overexpression and metastasis in breast cancer.Proteomics - Clin Appl. 2008; 2: 1313-1326
- AGR2 associates with HER2 expression predicting poor outcome in subset of estrogen receptor negative breast cancer patients.Exp Mol Pathol. 2017; 102: 280-283
Article info
Publication history
Published online: July 25, 2021
Accepted:
July 18,
2021
Received in revised form:
July 10,
2021
Received:
March 4,
2021
Footnotes
C.L.M and N.C.M contributed equally to this work.
Identification
Copyright
© 2021 Elsevier Inc. All rights reserved.
