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. 2022 Oct 25;24(1):70.
doi: 10.1186/s13058-022-01569-1.

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Tian Du #  1   2 , Lu Pan #  1   3 , Chengyou Zheng #  1   3 , Keming Chen  1   3 , Yuanzhong Yang  1   3 , Jiewei Chen  1   3 , Xue Chao  1   3 , Mei Li  1   3 , Jiabin Lu  1   3 , Rongzhen Luo  1   3 , Jinhui Zhang  1   3 , Yu Wu  1   3 , Jiehua He  4   5 , Dongping Jiang  6   7 , Peng Sun  8   9
Affiliations

Matrix Gla protein (MGP), GATA3, and TRPS1: a novel diagnostic panel to determine breast origin

Tian Du et al. Breast Cancer Res. .

Abstract

Background: Metastatic breast carcinoma is commonly considered during differential diagnosis when metastatic disease is detected in females. In addition to the tumor morphology and documented clinical history, sensitive and specific immunohistochemical (IHC) markers such as GCDFP-15, mammaglobin, and GATA3 are helpful for determining breast origin. However, these markers are reported to show lower sensitivity in certain subtypes, such as triple-negative breast cancer (TNBC).

Materials and methods: Using bioinformatics analyses, we identified a potential diagnostic panel to determine breast origin: matrix Gla protein (MGP), transcriptional repressor GATA binding 1 (TRPS1), and GATA-binding protein 3 (GATA3). We compared MGP, TRPS1, and GATA3 expression in different subtypes of breast carcinoma of (n = 1201) using IHC. As a newly identified marker, MGP expression was also evaluated in solid tumors (n = 2384) and normal tissues (n = 1351) from different organs.

Results: MGP and TRPS1 had comparable positive expression in HER2-positive (91.2% vs. 92.0%, p = 0.79) and TNBC subtypes (87.3% vs. 91.2%, p = 0.18). GATA3 expression was lower than MGP (p < 0.001) or TRPS1 (p < 0.001), especially in HER2-positive (77.0%, p < 0.001) and TNBC (43.3%, p < 0.001) subtypes. TRPS1 had the highest positivity rate (97.9%) in metaplastic TNBCs, followed by MGP (88.6%), while only 47.1% of metaplastic TNBCs were positive for GATA3. When using MGP, GATA3, and TRPS1 as a novel IHC panel, 93.0% of breast carcinomas were positive for at least two markers, and only 9 cases were negative for all three markers. MGP was detected in 36 cases (3.0%) that were negative for both GATA3 and TRPS1. MGP showed mild-to-moderate positive expression in normal hepatocytes, renal tubules, as well as 31.1% (99/318) of hepatocellular carcinomas. Rare cases (0.6-5%) had focal MGP expression in renal, ovarian, lung, urothelial, and cholangiocarcinomas.

Conclusions: Our findings suggest that MGP is a newly identified sensitive IHC marker to support breast origin. MGP, TRPS1, and GATA3 could be applied as a reliable diagnostic panel to determine breast origin in clinical practice.

Keywords: Breast carcinoma; GATA3; Immunohistochemical; MGP; TRPS1.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
GATA3, TRPS1, and MGP expression in benign breast ducts and breast cancer. GATA3 and TRPS1 showed nuclear staining and MGP showed cytoplasmic staining in the benign ductal epithelial cells (A). Representative immunostaining images showing high (B), moderate (C), and mild (D) expression of GATA3, TRPS1, and MGP
Fig. 2
Fig. 2
Schematic showing the selection of the breast-specific candidate markers using bioinformatic approach
Fig. 3
Fig. 3
The mRNA levels of candidate genes in different subtypes of breast cancer. LumA, luminal A; LumB, luminal B; Her2, Her2-enriched; Basal, basal-like; Normal, normal-like
Fig. 4
Fig. 4
Representative cases showing the combined positive using GATA3, TRPS1, and MGP panel in breast cancer. Case 1 shows an ER/PR+ invasive breast carcinoma with high expression of GATA3, TRPS1, and MGP. Case 2 shows a triple-negative invasive breast carcinoma with high expression of TRPS1, moderate expression of MGP, and negative expression of GATA3. Case 3 shows a HER2-positive (3+) invasive micropapillary carcinoma with high expression of MGP, mild expression of GATA3, and negative expression of TRPS1. Case 4 shows an ER/PR+ invasive breast carcinoma with high expression of GATA3, moderate expression of TRPS1, and negative expression of MGP. Case 5 shows a triple-negative invasive breast carcinoma with high expression of TRPS1, but negative expression of GATA3 and MGP. Case 6 shows a triple-negative invasive breast carcinoma with moderate expression of MGP, but negative expression of GATA3 and TRPS1
Fig. 5
Fig. 5
Representative cases showing the combined positive using GATA3, TRPS1, and MGP panel in metaplastic breast carcinomas. Case 1 shows a metaplastic squamous cell carcinoma with high expression of GATA3, MGP, and TRPS1. Case 2 shows a metaplastic breast carcinoma with chondrogenic differentiation and high expression of GATA3, MGP, and TRPS1. Case 3 shows a metaplastic breast carcinoma with chondrogenic differentiation which exhibits high expression of MGP and TRPS1, but negative for GATA3. Case 4 shows a high-grade spindle cell carcinoma with high expression of TRPS1, and negative expression of GATA3 and MGP. Case 5 shows a metaplastic squamous cell carcinoma with moderate expression of MGP, but negative expression of GATA3 and TRPS1
Fig. 6
Fig. 6
MGP expression in other solid tumors and normal tissues. MGP showed constant moderate expression in normal hepatocytes (A) and renal tubules (C). Mild-to-moderate expression of MGP was found in 31.1% of hepatocellular carcinoma (B). Rare cases (0.6–5%) had focal MGP expression in renal cell carcinoma (D), ovarian carcinoma (E), lung adenocarcinoma (F), urothelial carcinoma (G), and cholangiocarcinoma (H)
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