Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data

Sun, Xu; Zhang, Gan‐Lin; Nian, Jiayun; Yu, Mingwei; Chen, Shijian; Zhang, Yi; Yang, Guowang; Yang, Lin; Cheng, Pei-Yu; Chen, Yan; Ma, You-Zhi; Meng, Hui; Wang, Xiaomin; Li, Jinping

doi:10.18632/oncotarget.16575

Cited by 38 publications

(28 citation statements)

References 50 publications

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“…The same principles are also relevant to breast cancer. Heparanase is undetected in normal breast epithelium but its expression is induced in human breast carcinoma, associated with increased tumor metastasis and larger tumor size [ 15 – 17 ]. Similarly, overexpression of heparanase promotes, while anti-heparanase siRNA decreases the growth, angiogenesis, and metastasis of breast carcinoma cells [ 18 – 20 ].…”

Section: Introductionmentioning

confidence: 99%

“…Similarly, overexpression of heparanase promotes, while anti-heparanase siRNA decreases the growth, angiogenesis, and metastasis of breast carcinoma cells [ 18 – 20 ]. In addition, heparanase inhibitors were found to efficiently attenuate the tumorigenic capacity of breast carcinoma cells [ 21 , 22 ], altogether implying that heparanase plays a decisive role in breast cancer [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

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Prognostic significance of heparanase expression in primary and metastatic breast carcinoma

et al. 2017

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High levels of heparanase are detected in many types of tumors, associated with bad prognosis. Typically, heparanase levels are evaluated in a biopsy taken from the primary lesion, whereas its expression by the resulting metastases is most often unresolved. This becomes critically important as anti-heparanase compounds enter advanced clinical trials. Here, we examined the expression of heparanase in pairs of primary and the resulting distant metastases of breast carcinoma. Interestingly, we found that heparanase expression in the metastatic lesion does not always reflect its expression in the primary tumor. Accordingly, in some cases, the primary lesion was stained positive for heparanase while the metastasis stained negative, and vice versa. Heparanase discordance occurred in 38% of the patients, higher than that reported for hormone receptors, and was associated with bad prognosis. Thus, examination of heparanase levels in the tumor metastases should be evaluated for most efficient precision medicine applying heparanase inhibitors. Furthermore, we found that in stage I breast cancer patients strong heparanase staining is associated with shorter overall survival. Thus, heparanase levels can assist in the diagnosis and in determining the necessity and type of treatment in early stage breast cancer.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prognostic significance of heparanase expression in primary and metastatic breast carcinoma

et al. 2017

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“…We then investigated the mechanism underlying the differences in cell clusters formation in the various cell lines. Heparanase is an endoglycosidase that up-regulated in breast cancer and associated with elevated metastasis, advanced histological grade, and poor survival [21] . We hence detected heparanase expression in these cell lines.…”

Section: Resultsmentioning

confidence: 99%

CTC clusters induced by heparanase enhance breast cancer metastasis

et al. 2018

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Aggregated metastatic cancer cells, referred to as circulating tumor cell (CTC) clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase (HPSE). Heparanase induced FAK- and ICAM-1-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

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“…HPSE expression strongly correlates with poor survival in BC (Sun, Zhang et al 2017) and serum levels of shed SDC1 have been identified to be informative in regards to progression of several cancers including breast (Joensuu, Anttonen et al 2002, Vassilakopoulos, Kyrtsonis et al 2005, Szarvas, Reis et al 2016. Shed SDC1 abundance detected in serum has been associated with BC size (Malek-Hosseini, Jelodar et al 2017), and to be a result of chemotherapy (Ramani and Sanderson 2014).…”

Section: Introductionmentioning

confidence: 99%

Heparanase promotes Syndecan-1 expression to mediate fibrillar collagen and mammographic density in human breast tissue culturedex vivo

Huang

Reye

Momot

et al. 2020

Preprint

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max 350)Mammographic density (MD) is a strong and independent factor for breast cancer (BC) risk and is increasingly associated with BC progression. We have previously shown in mice that high MD, which is characterised by the preponderance of a fibrous stroma, facilitates BC xenograft growth and metastasis. This stroma is rich in extracellular matrix (ECM) factors, including heparan sulfate proteoglycans (HSPGs), such as the BC-associated syndecan-1 (SDC1). These proteoglycans tether growth factors, which are released by heparanase (HPSE). MD is positively associated with estrogen exposure and, in cell models, estrogen has been implicated in the upregulation of HPSE, the activity 2 of which promotes SDC expression. Herein we describe a novel measurement approach (single-sided NMR) using a patient-derived explant (PDE) model of normal human (female) mammary tissue cultured ex vivo to investigate the role(s) of HPSE and SDC1 on MD. Relative HSPG gene and protein analyses determined in patient-paired high versus low MD tissues identified SDC1 and SDC4 as potential mediators of MD. Using the PDE model we demonstrate that HPSE promotes SDC1 rather than SDC4 expression and cleavage, leading to increased MD. In this model system, synstatin (SSTN), an SDC1 inhibitory peptide designed to decouple SDC1-ITGv3 parallel collagen alignment, reduced the abundance of fibrillar collagen as assessed by picrosirius red viewed under polarised light, and reduced MD. Our results reveal a potential role for HPSE in maintaining MD via its direct regulation of SDC1, which in turn physically tethers collagen into aligned fibres characteristic of MD. We propose that inhibitors of HPSE and/or SDC1 may afford an opportunity to reduce MD in high BC risk individuals and reduce MD-associated BC progression in conjunction with established BC therapies.

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Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data

Cited by 38 publications

References 50 publications

Prognostic significance of heparanase expression in primary and metastatic breast carcinoma

Prognostic significance of heparanase expression in primary and metastatic breast carcinoma

CTC clusters induced by heparanase enhance breast cancer metastasis

Heparanase promotes Syndecan-1 expression to mediate fibrillar collagen and mammographic density in human breast tissue culturedex vivo

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