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International Journal of Clinical Oncology
Published in: International Journal of Clinical Oncology 4/2024

27-02-2024 | Breast Cancer | Original Article

Plasma THBS1 as a predictive biomarker for poor prognosis and brain metastasis in patients with HER2-enriched breast cancer

Authors: Yang Li, Jun Qin, Guiming Chen, Weidong Wu, Xing Sun

Published in: International Journal of Clinical Oncology | Issue 4/2024

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Abstract

Background

Thrombospondin-1 (THBS1) is a secretory adhesive glycoprotein involved in the progression of multiple malignancies, including breast cancer. However, the clinical significance and prognostic role of plasma THBS1 in breast cancer have yet to be clarified.

Methods

Plasma THBS1 levels in 627 breast cancer patients were analyzed by enzyme-linked immunosorbent assay. Bone marrow blood was drawn from the anterior/posterior superior iliac spine to detect the presence of disseminated tumor cells (DTCs). The effects of plasma THBS1 on the clinicopathological characteristics and survival prediction of breast cancer patients were explored.

Results

Plasma THBS1 did not correlate with overall survival, breast cancer-specific survival (BCSS), and distant disease-free survival (DDFS) in the entire breast cancer cohort. Notably, HER2-enriched patients with high-plasma THBS1 levels had significantly shorter BCSS (P = 0.027) and DDFS (P = 0.011) than those with low levels. Multivariate analyses revealed that plasma THBS1 was an independent prognostic marker of BCSS (P = 0.026) and DDFS (P = 0.007) in HER2-enriched patients. THBS1 levels were 24% higher in positive DTC patients than in negative DTC patients (P = 0.031), and high levels were significantly associated with poor BCSS in positive DTC patients (HR 2.08, 95% CI 1.17–3.71; P = 0.019). Moreover, high-plasma THBS1 levels were specifically associated with an increased occurrence of brain metastasis in HER2-enriched patients (P = 0.041).

Conclusion

These findings suggest that plasma THBS1 may be serving as an unfavorable prognosis predictor for HER2-enriched breast cancer and justifies the need for further research.
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Literature
1.
Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249CrossRefPubMed
2.
3.
4.
5.
Harrell JC, Prat A, Parker JS et al (2012) Genomic analysis identifies unique signatures predictive of brain, lung, and liver relapse. Breast Cancer Res Treat 132:523–535PubMedCrossRef
6.
Muth M, Engelhardt BM, Kröger N et al (2011) Thrombospondin-1 (TSP-1) in primary myelofibrosis (PMF) - a megakaryocyte-derived biomarker which largely discriminates PMF from essential thrombocythemia. Ann Hematol 90:33–40PubMedCrossRef
7.
Khaiboullina SF, Morzunov SP, St Jeor SC et al (2016) Hantavirus infection suppresses thrombospondin-1 expression in cultured endothelial cells in a strain-specific manner. Front Microbiol 7:1077PubMedPubMedCentralCrossRef
8.
Zhou L, Picard D, Ra YS et al (2010) Silencing of thrombospondin-1 is critical for myc-induced metastatic phenotypes in medulloblastoma. Cancer Res 70:8199–8210PubMedCrossRef
9.
Yee KO, Streit M, Hawighorst T et al (2004) Expression of the type-1 repeats of thrombospondin-1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol 165:541–552PubMedPubMedCentralCrossRef
10.
11.
Martin-Manso G, Galli S, Ridnour LA et al (2008) Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells. Cancer Res 68:7090–7099PubMedPubMedCentralCrossRef
12.
Incardona F, Lewalle JM, Morandi V et al (1995) Thrombospondin modulates human breast adenocarcinoma cell adhesion to human vascular endothelial cells. Cancer Res 55:166–173PubMed
13.
Perez-Janices N, Blanco-Luquin I, Tuñón MT et al (2015) EPB41L3, TSP-1 and RASSF2 as new clinically relevant prognostic biomarkers in diffuse gliomas. Oncotarget 6:368–380PubMedPubMedCentralCrossRef
14.
Borsotti P, Ghilardi C, Ostano P et al (2015) Thrombospondin-1 is part of a Slug-independent motility and metastatic program in cutaneous melanoma, in association with VEGFR-1 and FGF-2. Pigment Cell Melanoma Res 28:73–81PubMedCrossRef
15.
Lyu T, Jia N, Wang J et al (2013) Expression and epigenetic regulation of angiogenesis-related factors during dormancy and recurrent growth of ovarian carcinoma. Epigenetics 8:1330–1346PubMedPubMedCentralCrossRef
16.
Nie S, Lo A, Wu J et al (2014) Glycoprotein biomarker panel for pancreatic cancer discovered by quantitative proteomics analysis. J Proteome Res 13:1873–1884PubMedPubMedCentralCrossRef
17.
Ioachim E, Damala K, Tsanou E et al (2012) Thrombospondin-1 expression in breast cancer: prognostic significance and association with p53 alterations, tumour angiogenesis and extracellular matrix components. Histol Histopathol 27:209–216PubMed
18.
Weinstat-Saslow DL, Zabrenetzky VS, VanHoutte K et al (1994) Transfection of thrombospondin 1 complementary DNA into a human breast carcinoma cell line reduces primary tumor growth, metastatic potential, and angiogenesis. Cancer Res 54:6504–6511PubMed
19.
Mo D, He F, Zheng J et al (2021) tRNA-derived fragment tRF-17-79MP9PP attenuates cell invasion and migration via THBS1/TGF-β1/Smad3 axis in breast cancer. Front Oncol 11:656078PubMedPubMedCentralCrossRef
20.
Wang T, Srivastava S, Hartman M et al (2016) High expression of intratumoral stromal proteins is associated with chemotherapy resistance in breast cancer. Oncotarget 7:55155–55168PubMedPubMedCentralCrossRef
21.
Marcheteau E, Farge T, Pérès M et al (2021) Thrombospondin-1 silencing improves lymphocyte infiltration in tumors and response to anti-PD-1 in triple-negative breast cancer. Cancers (Basel) 13:4059PubMedCrossRef
22.
Rouanne M, Adam J, Goubar A et al (2016) Osteopontin and thrombospondin-1 play opposite roles in promoting tumor aggressiveness of primary resected non-small cell lung cancer. BMC Cancer 16:483PubMedPubMedCentralCrossRef
23.
Zhu L, Li Q, Wang X et al (2019) THBS1 is a novel serum prognostic factors of acute myeloid leukemia. Front Oncol 9:1567PubMedCrossRef
24.
Hu XY, Ling ZN, Hong LL et al (2021) Circulating methylated THBS1 DNAs as a novel marker for predicting peritoneal dissemination in gastric cancer. J Clin Lab Anal 35:e23936PubMedPubMedCentralCrossRef
25.
Suh EJ, Kabir MH, Kang UB et al (2012) Comparative profiling of plasma proteome from breast cancer patients reveals thrombospondin-1 and BRWD3 as serological biomarkers. Exp Mol Med 44:36–44PubMedCrossRef
26.
Byrne GJ, Hayden KE, McDowell G et al (2007) Angiogenic characteristics of circulating and tumoural thrombospondin-1 in breast cancer. Int J Oncol 31:1127–1132PubMed
27.
Goldhirsch A, Winer EP, Coates AS et al (2013) Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol 24:2206–2223PubMedPubMedCentralCrossRef
28.
Hayden K, Tetlow L, Byrne G et al (2000) Radioimmunoassay for the measurement of thrombospondin in plasma and breast cyst fluid: validation and clinical application. Ann Clin Biochem 37:319–325PubMedCrossRef
29.
Sutherland DR, Anderson L, Keeney M et al (1996) The ISHAGE guidelines for CD34+ cell determination by flow cytometry. International Society of Hematotherapy and Graft Engineering. J Hematother 5:213–226PubMedCrossRef
30.
Cerami E, Gao J, Dogrusoz U et al (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404PubMedCrossRef
31.
Behrens J, Frixen U, Schipper J et al (1992) Cell adhesion in invasion and metastasis. Semin Cell Biol 3:169–178PubMedCrossRef
32.
33.
Shen J, Cao B, Wang Y et al (2018) Hippo component YAP promotes focal adhesion and tumour aggressiveness via transcriptionally activating THBS1/FAK signalling in breast cancer. J Exp Clin Cancer Res 37:175PubMedPubMedCentralCrossRef
34.
Murphy-Ullrich JE, Höök M (1989) Thrombospondin modulates focal adhesions in endothelial cells. J Cell Biol 109:1309–1319PubMedCrossRef
35.
Orr AW, Pallero MA, Murphy-Ullrich JE (2002) Thrombospondin stimulates focal adhesion disassembly through Gi- and phosphoinositide 3-kinase-dependent ERK activation. J Biol Chem 277:20453–20460PubMedCrossRef
36.
Cen J, Feng L, Ke H et al (2019) Exosomal thrombospondin-1 disrupts the integrity of endothelial intercellular junctions to facilitate breast cancer cell metastasis. Cancers (Basel) 11
37.
Hartkopf AD, Wallwiener M, Fehm TN et al (2015) Disseminated tumor cells from the bone marrow of patients with nonmetastatic primary breast cancer are predictive of locoregional relapse. Ann Oncol 26:1155–1160PubMedCrossRef
38.
Braun S, Vogl FD, Naume B et al (2005) A pooled analysis of bone marrow micrometastasis in breast cancer. N Engl J Med 353:793–802PubMedCrossRef
39.
40.
Liu X, Jin J, Liu Y et al (2021) Targeting TSP-1 decreased periodontitis by attenuating extracellular matrix degradation and alveolar bone destruction. Int Immunopharmacol 96:107618PubMedCrossRef
41.
42.
Wen XF, Yang G, Mao W et al (2006) HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: implications for HER2-targeted antibody therapy. Oncogene 25:6986–6996PubMedCrossRef
43.
Widner DB, Park SH, Eber MR et al (2018) Interactions between disseminated tumor cells and bone marrow stromal cells regulate tumor dormancy. Curr Osteoporos Rep 16:596–602PubMedPubMedCentralCrossRef
44.
Yang G, Cai KQ, Thompson-Lanza JA et al (2004) Inhibition of breast and ovarian tumor growth through multiple signaling pathways by using retrovirus-mediated small interfering RNA against Her-2/neu gene expression. J Biol Chem 279:4339–4345PubMedCrossRef
45.
del Barco BI, Nebreda AR (2012) Roles of p38 MAPKs in invasion and metastasis. Biochem Soc Trans 40:79–84CrossRef
46.
47.
Zhao HY, Ooyama A, Yamamoto M et al (2008) Molecular basis for the induction of an angiogenesis inhibitor, thrombospondin-1, by 5-fluorouracil. Cancer Res 68:7035–7041PubMedCrossRef
48.
Wang G, Wang J, Chang A et al (2020) Her2 promotes early dissemination of breast cancer by suppressing the p38 pathway through Skp2-mediated proteasomal degradation of Tpl2. Oncogene 39:7034–7050PubMedPubMedCentralCrossRef
49.
Le XF, Lammayot A, Gold D et al (2005) Genes affecting the cell cycle, growth, maintenance, and drug sensitivity are preferentially regulated by anti-HER2 antibody through phosphatidylinositol 3-kinase-AKT signaling. J Biol Chem 280:2092–2104PubMedCrossRef
50.
Izumi Y, Xu L, di Tomaso E et al (2002) Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature 416:279–280PubMedCrossRef
51.
Yee KO, Connolly CM, Duquette M et al (2009) The effect of thrombospondin-1 on breast cancer metastasis. Breast Cancer Res Treat 114:85–96PubMedCrossRef
52.
Miller TW, Kaur S, Ivins-O’Keefe K et al (2013) Thrombospondin-1 is a CD47-dependent endogenous inhibitor of hydrogen sulfide signaling in T cell activation. Matrix Biol 32:316–324PubMedPubMedCentralCrossRef
53.
Kennecke H, Yerushalmi R, Woods R et al (2010) Metastatic behavior of breast cancer subtypes. J Clin Oncol 28:3271–3277PubMedCrossRef
54.
Zagar TM, Van Swearingen AE, Kaidar-Person O et al (2016) Multidisciplinary management of breast cancer brain metastases. Oncology (Williston Park) 30:923–933PubMed
55.
Wang TN, Qian X, Granick MS et al (1996) Thrombospondin-1 (TSP-1) promotes the invasive properties of human breast cancer. J Surg Res 63:39–43PubMedCrossRef
56.
Anastasi F, Greco F, Dilillo M et al (2020) Proteomics analysis of serum small extracellular vesicles for the longitudinal study of a glioblastoma multiforme mouse model. Sci Rep 10:20498PubMedPubMedCentralCrossRef
57.
Kircher DA, Trombetti KA, Silvis MR et al (2019) AKT1(E17K) activates focal adhesion kinase and promotes melanoma brain metastasis. Mol Cancer Res 17:1787–1800PubMedPubMedCentralCrossRef
58.
Priego N, Zhu L, Monteiro C et al (2018) STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis. Nat Med 24:1024–1035PubMedCrossRef
59.
Chen CY, Chao YM, Lin HF et al (2020) miR-195 reduces age-related blood-brain barrier leakage caused by thrombospondin-1-mediated selective autophagy. Aging Cell 19:e13236PubMedPubMedCentralCrossRef
60.
Rege TA, Stewart J Jr, Dranka B et al (2009) Thrombospondin-1-induced apoptosis of brain microvascular endothelial cells can be mediated by TNF-R1. J Cell Physiol 218:94–103PubMedPubMedCentralCrossRef
61.
Meijles DN, Sahoo S, Al Ghouleh I et al (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:eaaj1784PubMedPubMedCentralCrossRef
62.
Alaoui-Jamali MA, Song DJ, Benlimame N et al (2003) Regulation of multiple tumor microenvironment markers by overexpression of single or paired combinations of ErbB receptors. Cancer Res 63:3764–3774PubMed
63.
Metadata
Title
Plasma THBS1 as a predictive biomarker for poor prognosis and brain metastasis in patients with HER2-enriched breast cancer
Authors
Yang Li
Jun Qin
Guiming Chen
Weidong Wu
Xing Sun
Publication date
27-02-2024
Publisher
Springer Nature Singapore
Published in
International Journal of Clinical Oncology / Issue 4/2024
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-024-02472-9

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