TRPS1 drives heterochromatic origin refiring and cancer genome evolution

Yang, Jianguo; Li, Xiaoping; Huang, Yunchao; He, Lin; Zhang, Wenting; Ren, Jie; Wang, Yue; Wu, Jiyue; Wu, Xiaodi; Lin, Shuo; Yang, Xiaohan; Sun, Luyang; Liang, Jing; Shang, Yongfeng

doi:10.1016/j.celrep.2021.108814

Cited by 20 publications

(9 citation statements)

References 110 publications

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“…TRPS1 is reported to be a transcriptional repressor that binds specifically to GATA sequences and represses the expression of GATA-regulated genes which function in vertebrate development, especially in the process of chondrocyte proliferation and differentiation [ 41 , 42 ]. Some studies have suggested that TRPS1 may also act as a critical modulator in mammary epithelial cell growth, differentiation, and breast cancer development via epithelial–mesenchymal transformation, DNA replication, and mitosis [ 43 , 44 ]. A recent study by Ai et al reported that TRPS1 could serve as a sensitive and specific marker for breast carcinomas [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

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

Zheng

et al. 2022

Breast Cancer Res

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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.

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Section: Discussionmentioning

confidence: 99%

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

Zheng

et al. 2022

Breast Cancer Res

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“…TRPS1 is a transcription factor classically linked to skeletal development, as subjects with germline alterations in the Trps1 gene suffer from autosomal dominant trichorhinophalangeal syndromes with characteristic craniofacial abnormalities (Lüdecke et al, 2001; Momeni et al, 2000). More recently, TRPS1 has been implicated in tumorigenesis in breast cancer (Ai et al, 2021; Cornelissen et al, 2020) and osteosarcoma (Li et al, 2015) potentially through promotion of dysregulated cell replication resulting in accumulation of genomic aberrations (Yang et al, 2021). Functionally, TRPS1 is thought to function uniquely as a transcriptional repressor via its GATA domain (Malik et al, 2002), although notably TRPS1 contains two Ikaros-like domains whose specific functions are poorly characterized.…”

Section: Discussionmentioning

confidence: 99%

Systematic Elucidation and Pharmacological Targeting of Tumor-Infiltrating Regulatory T Cell Master Regulators

Obradovic

Ager

Turunen

et al. 2022

Preprint

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Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive therapeutic targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate Master Regulators (MRs), predicted to mechanistically regulate TI-Tregs transcriptional state. In vivo, pooled CRISPR-KO screening, using a hematopoietic stem cell transplant model, confirmed essentiality of 7 of 17 MRs in TI-Treg recruitment and/or retention to the TME, without affecting other T cell subtypes, while individual knockout of the most significant MR (TRPS1) significantly reduced tumor allograft growth. TI-Treg drug perturbation profile analysis identified drugs capable of inverting the TI-Treg-specific MR activity signature at low concentration. Low dose treatment with gemcitabine (top prediction) inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased PD-1 inhibitor efficacy, and depleted TI-Tregs in vivo. The study provides key insight into Treg infiltration mechanism and a gene reporter assay to identify additional small molecule inhibitors.Graphical Abstract

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“…Earlier studies also reported a high sensitivity and specificity of TRPS1 for primary extramammary Paget disease, 44 and differential staining of TRPS1 in various types of malignant and benign cutaneous sweat glands. 45 Several studies have proposed oncogenic 46,47 or tumor suppressive 5,6 roles for TRPS1. The availability of clinic-pathologic data for several tumor cohorts enabled us to interrogate the potential clinical significance of aberrant TRPS1 expression in vivo.…”

Section: Discussionmentioning

confidence: 99%

TRPS1 is a Highly Sensitive Marker for Breast Cancer

Lennartz,

Löhr,

Höflmayer

et al. 2024

American Journal of Surgical Pathology

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Trichorhinophalangeal syndrome 1 (TRPS1) is a nuclear protein highly expressed in breast epithelial cells. TRPS1 immunohistochemistry (IHC) has been suggested as a breast cancer marker. To determine the diagnostic and prognostic utility of TRPS1 IHC, tissue microarrays containing 19,201 samples from 152 different tumor types and subtypes were analyzed. GATA3 IHC was performed in a previous study. TRPS1 staining was seen in 86 of 152 tumor categories with 36 containing at least one strongly positive case. TRPS1 staining predominated in various types of breast carcinomas (51%-100%), soft tissue tumors (up to 100%), salivary gland tumors (up to 46%), squamous cell carcinomas (up to 35%), and gynecological cancers (up to 40%). TRPS1 positivity occurred in 1.8% of 1083 urothelial neoplasms. In invasive breast carcinoma of no special type, low TRPS1 expression was linked to high grade (P= 0.0547), high pT (P< 0.0001), nodal metastasis (P= 0.0571), loss of estrogen receptor and progesterone receptor expression (P< 0.0001 each), and triple-negative status (P< 0.0001) but was unrelated to patient survival (P= 0.8016). In squamous cell carcinomas from 11 different sites, low TRPS1 expression was unrelated to tumor phenotype. Positivity for both TRPS1 and GATA3 occurred in 47.4% to 100% of breast cancers, up to 30% of salivary gland tumors, and 29 (0.3%) of 9835 tumors from 134 other cancer entities. TRPS1 IHC has high utility for the identification of cancers of breast (or salivary gland) origin, especially in combination with GATA3. The virtual absence of TRPS1 positivity in urothelial neoplasms is useful for the distinction of GATA3-positive urothelial carcinoma from breast cancer.

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TRPS1 drives heterochromatic origin refiring and cancer genome evolution

Cited by 20 publications

References 110 publications

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

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

Systematic Elucidation and Pharmacological Targeting of Tumor-Infiltrating Regulatory T Cell Master Regulators

TRPS1 is a Highly Sensitive Marker for Breast Cancer

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