Impacto prognóstico da expressão da proteína AGR3 no câncer de mama: Uma revisão sistemática e metanálise

Moraes, Carolina Leão de; Mendonça, Carolina Rodrigues; Melo, Natália Cruz e; Tacon, Fernanda Sardinha de Abreu; Melo Junior, Jair Pereira de; Amaral, Waldemar Naves do

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Revista Brasileira de Ginecologia e Obstetrícia

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Sumário

Review Article • Rev Bras Ginecol Obstet 45 (10) • 2023 • https://doi.org/10.1055/s-0043-1772183 copiar

Impacto prognóstico da expressão da proteína AGR3 no câncer de mama: Uma revisão sistemática e metanálise

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Objetivo

Investigar o significado clinicopatológico e prognóstico da expressão da proteína anterior gradient 3 (AGR3) em mulheres com câncer de mama.

Fontes de Dados

Utilizamos as bases de dados PubMed, CINAHL, EMBASE, Scopus e Web of Science para pesquisar estudos em inglês, sem restrições quanto ao ano de publicação. Os termos buscados foram: breast cancer AND anterior gradient 3 OR AGR3 expression.

Seleção dos Estudos

Foram incluídos estudos observacionais ou intervencionais, estudos sobre a expressão da proteína AGR3 por imuno-histoquímica, e estudos sobre câncer de mama invasivo. Excluíram-se relatos de casos, estudos com animais e revisões. Quatro estudos foram selecionados, que continham 713 casos de câncer de mama.

Coleta de Dados

Foram extraídos dados relativos a características clinicopatológicas e sobrevida. A metanálise da prevalência da expressão de AGR3 foi realizada conforme as características clinicopatológicas, razões de risco (RRs) e sobrevida global (SG) e sobrevida livre de doença (SLD).

Síntese dos Dados

Encontrou-se expressão de AGR3 em 62% dos casos, que se associou com grau histológico II, positividade de receptores de estrogênio e progesterona, baixa expressão de ki67, recorrência ou metástase à distância e subtipos luminais. Em pacientes com graus histológicos baixo e intermediário, a expressão de AGR3 conferiu pior SG (RR: 2,39; intervalo de confiança de 95% [IC95%]: 0,628–4,159; p = 0,008) e pior SLD (RR: 3,856; IC95%: 1,026–6,686; p = 0,008).

Conclusão

A AGR3 pode ser um biomarcador para a detecção precoce do câncer de mama e predizer o prognóstico em subtipos luminais. Em graus histológicos baixo e intermediário, a expressão da proteína AGR3 pode indicar um prognóstico desfavorável em relação à sobrevida.

Palavras-chave
câncer de mama; proteína humana AGR3; imuno-histoquímica; prognóstico; sobrevida

Databases	Search Strategy
MEDLINE/PubMed	Search: (“breast neoplasms”[MeSH Terms] OR (“breast”[All Fields] AND “neoplasms”[All Fields]) OR “breast neoplasms”[All Fields] OR (“breast”[All Fields] AND “cancer”[All Fields]) OR “breast cancer”[All Fields]) AND (((“anterior”[All Fields] OR “anteriores”[All Fields] OR “anteriorization”[All Fields] OR “anteriorized”[All Fields] OR “anteriors”[All Fields]) AND (“gradient”[All Fields] OR “gradient s”[All Fields] OR “gradients”[All Fields]) AND “3”[All Fields]) OR (“AGR3”[All Fields] AND (“express”[All Fields] OR “expresse”[All Fields] OR “expresses”[All Fields] OR “expressing”[All Fields] OR “expressions”[All Fields] OR “gene expression”[MeSH Terms] OR (“gene”[All Fields] AND “expression”[All Fields]) OR “gene expression”[All Fields] OR “expressed”[All Fields] OR “expression”[All Fields]))) Total: 32
CINAHL	Boolean/Phrase: Breast Cancer AND AGR3 OR Anterior gradient 3 Total: 3
EMBASE	1 breast cancer/394079
	2 Anterior gradient 3.mp./12
	3 AGR3.mp./94
	4 2 or 3/94
	5 1 and 4/12
	Total: 12
Scopus	TITLE-ABS-KEY ((breast cancer) AND (Anterior gradient 3 OR AGR3))
	Total: 29
Web of Science	((breast cancer) AND (AGR3 OR Anterior gradient 3))
	Total: 40

Number	Title	Reason for exclusion
1	Jian, Lei et al. AGR3 promotes estrogen receptor-positive breast cancer cell proliferation in an estrogen-dependent manner. Oncology Letters, v. 20, n. 2, p. 1,441–1,451, 2020.	Another outcome
2	Umesh, Anita et al. Identification of AGR3 as a potential biomarker though public genomic data analysis of triple-negative (TN) versus triple-positive (TP) breast cancer (BC). Journal of Clinical Oncology, v. 30, n. 27, supplement 31, 2012.	Another outcome
3	Obacz, Joanna et al. The role of AGR2 and AGR3 in cancer: similar but not identical. European Journal of Cell Biology, v. 94, n. 3–4, p. 139–147, 2015.	Another outcome
4	Obacz, Joanna et al. Extracellular AGR3 regulates breast cancer cells migration via Src signaling. Oncology Letters, v. 18, n. 5, p. 4,449–4,456, 2019.	Another outcome
5	PERSSON, Staffan et al. Diversity of the protein disulfide isomerase family: identification of breast tumor induced Hag2 and Hag3 as novel members of the protein family. Molecular Phylogenetics and Evolution, v. 36, n. 3, p. 734–740, 2005.	Another outcome

Reference	N/age	Study design/ follow-up	Immunohistochemical staining	AGR3 expression	Conflict of interests	Ethical approval	Quality of the evidence (GRADE)
Obacz et al., 2015⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532 (Czech Republic)	129/29 to 84 (median: 57) years	Cohort/ 10 years	Tumor samples were fixed in 10% neutral buffered formalin for 24 hours and then embedded in paraffin wax. Immunohistochemical analysis was performed on 4-μm thick sections cut from formalin-fixed paraffin-embedded archival tissue blocks, mounted on slides, deparaffinized in xylene, and rehydrated in phosphate-buffered saline through a graded ethanol series.	104/129	No	Yes	⊕⊕⊕⊝moderate
Fletcher et al., 2003¹⁰10 Fletcher GC, Patel S, Tyson K, Adam PJ, Schenker M, Loader JA, et al. 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(04):579–585 (United Kingdom)	58/< 50 years versus 50 years	Not reported	Immunohistochemical analysis was performed on formalin-fixed paraffin-embedded tissue microarrays containing 1-mm sections of breast carcinoma tissues from 60 donors. Slides were deparafinized by two 5-minute washes in xylene, then rehydrated through successive graded ethanol solutions and washed for 5 minutes in phosphate-buffered saline.	43/58	No	Yes	⊕⊕⊝⊝ Low
Garczyk et al., 2015¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106 (Germany)	190 Age: Less than 54,5 years of age versus 54,5 years	Cohort 138.5 (range: 1–218) months	Immunohistochemical analysis was performed according to the manufacturer's instructions (DAKO 5001; DAKO, Glostrup, Denmark). Heat-induced epitope retrieval was performed in 10-mM citrate buffer (pH 6.0) for 10 minutes using a pressure cooker. Formalin-fixed, paraffin-embedded sections (3 μm) were incubated for 45 minutes with mouse monoclonal anti-AGR3-antibody (1:1000; ab82400, Abcam, Cambridge, United Kingdom).	104/190	No	Yes	⊕⊕⊕⊝moderate
Xu et al., 2020¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245 (China)	336*/52 years, which ranged from 28 to 89 years	Cohort/ 5–146 months	All procedures were performed in Benchmark XT (Roche, Basel, Switzerland). Antigen retrieval was performed in citrate buffer at 121°C for 2 minutes 15 seconds. After retrieval, sections were steeped in 3% H2O2 buffer for 25 minutes and in 10% goat serum buffer for 25 minutes. Then, the sections were steeped in primary antibody against AGR3 (1:100, HPA053942, Sigma, St. Louis, MO, United States) at 4°C for 1 night.	129/336	No	Yes	⊕⊕⊕⊝moderate

Analysis		Proportion (%) Of AGR3	p-value for overall effect	Heterogeneity I ² (%)/p-value	References
Age (in years)
	< 50	0.44%	0.068	0%/p = 0.00	¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	≥ 50	0.34%	0.068	0%/p = 0.00
Histological grade
	I	0.44%	0.048	95.33%/p = 0.00	⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532, ¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106, ¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	II	0.65%
	III	0.24%
Estrogen receptor
	(–)	0.12%	0.000	98.53%/p = 0.00	⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532, ¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106, ¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	(+)	0.72%	0.000	98.53%/p = 0.00
Progesterone receptor
	(–)	0.22%	0.000	96.74%/p = 0.00	⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532, ¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106, ¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	(+)	0.69%	0.000	96.74%/p = 0.00
MIB1/Ki-67 expression
	Low	0.52%	0.015	90.16%/p = 0.00	⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532, ¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	High	0.41%	0.015	90.16%/p = 0.00
HER2
	(–)	0.60%	0.059	92.36%/p = 0.00	⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532, ¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106, ¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	(+)	0.33%	0.059	92.36%/p = 0.00
Recurrence or distant metastasis
	No	0.34%	0.001	.%, p = 0.00	¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	Yes	0.55%	0.001	.%, p = 0.00
Molecular subtypes
	Luminal A	0.46%	0.000	94.06%, p = 0.00	¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245
	Luminal B	0.48%
	HER2+	0.11%
	Triple-negative	0.15%

Global survival
Obacz et al., 2015⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532	Determination of overall survival by Kaplan–Meier analysis in patients with “high” AGR3 expression and patients with “low” AGR3 expression using Breslow test (p = 0.111).
Garczyk et al., 2015¹¹11 Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, et al. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One. 2015;10(04):e0122106	Patients with low and intermediate grade tumors showing high AGR3 expression had an unfavorable outcome (mean tumor-specific survival: 142.5 ± 9.6 months; 95%CI: 123.8–161.2) compared with those with low AGR3 expression (mean tumor-specific survival: 181.7 ± 10.1 months; 95%CI: 162.0–201.4). The Cox regression model confirmed AGR3 to be a putative independent marker of unfavorable prognosis in low- and intermediate-grade breast tumors (multivariate HR: 2.186; 95%CI: 1.008–4.740; p< 0.05).
Xu et al., 2020¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245	IDC patients of grades I-II: in the multivariate Cox regression analysis, we found that AGR3 expression was an independent predictor for overall survival (HR: 4.161; 95%CI: 1.406–12.312; p< 0.010).
Disease-free survival
Obacz et al., 2015⁵5 Obacz J, Brychtova V, Podhorec J, Fabian P, Dobes P, Vojtesek B, Hrstka R. Anterior gradient protein 3 is associated with less aggressive tumors and better outcome of breast cancer patients. OncoTargets Ther. 2015;8:1523–1532	Determination of progression-free survival by Kaplan–Meier analysis in patients with “high” AGR3 expression (more than 50% of positive cells) and patients with “low” AGR3 expression (less than 50% of positive cells) using Breslow test (p = 0.037)
Xu et al., 2020¹³13 Xu Q, Shao Y, Zhang J, Zhang H, Zhao Y, Liu X, et al. Anterior Gradient 3 Promotes Breast Cancer Development and Chemotherapy Response. Cancer Res Treat. 2020;52(01):218–245	IDC patients of grades I-II: in the multivariate Cox regression analysis, we found that AGR3 expression was an independent predictor for disease-free survival (HR: 3.856; 95%CI: 1.953–7.613; p< 0.001)

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[1] Address for correspondence Carolina Leão de Moraes, PhD, (e-mail: carolina.leao.moraes@gmail.com).