Clinical and Biological Significance of Hepsin Overexpression in Breast Cancer

Xing, Peng; Li, Ji‐Guang; Jin, Feng; Zhao, Tingting; Li, Qun; Dong, Huiting; Wei, Xiaolin

doi:10.2310/jim.0b013e31821451a1

Cited by 37 publications

(32 citation statements)

References 39 publications

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“…However, such cooperation remains to be demonstrated in mouse breast cancer models, preferably using inducible systems. Finally, Hepsin overexpression is a common genetic alteration in prostate and breast cancer (41,51), and thus a target for intensifying drug development efforts (52). The present study outlines an appropriate genetic and cellular context for biological validation of Hepsin as a potential therapeutic target in breast cancer.…”

Section: Reduced Lkb1 Expression Is Associated With Hepsin Deregulatimentioning

confidence: 93%

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

Partanen

Tervonen

Myllynen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

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Although loss of epithelial integrity is a hallmark of advanced cancer, it remains poorly understood whether genetic alterations corrupting this integrity causally facilitate tumorigenesis. We show that conditional deletion of tumor suppressor gene Lkb1 (Par-4) in the mammary gland compromises epithelial integrity manifested by mislocalization of cell polarity markers, lateralization of tight junctions, deterioration of desmosomes and basement membrane (BM), and hyperbranching of the mammary ductal tree. We identify the desmosomal BM remodelling serine protease Hepsin as a key factor mediating Lkb1 loss-induced structural alterations in mammary epithelium and BM fragmentation. Although loss of Lkb1 alone does not promote mammary tumorigenesis, combination of Lkb1 deficiency with oncogenic c-Myc leads to dramatic acceleration in tumor formation. The results coupling Lkb1 loss-mediated epithelial integrity defects to mislocalization of serine protease Hepsin and to oncogenic synergy with c-Myc imply that Lkb1 loss facilitates oncogenic proliferation by releasing epithelial cells from structural BM boundaries.breast cancer | mouse model

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Section: Reduced Lkb1 Expression Is Associated With Hepsin Deregulatimentioning

confidence: 93%

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

Partanen

Tervonen

Myllynen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Of the 46 putative OAs identified [27], B7-H4 [28], Claudin 3 [29], Hepsin [30], CD52 [31], and Desmoglein 2 [32] are Class I OAs, expressed on the plasma membrane of cancer and TME cells and therefore constitute promising targets for vaccination. Class II OAs are another group of identified OAs and includes cytokines and chemokines copiously released in the TME.…”

Section: The Urgency Of Defining the Most Promising Tme-associatedmentioning

confidence: 99%

Microenvironment, Oncoantigens, and Antitumor Vaccination: Lessons Learned from BALB-neuT Mice

Conti

Ruiu

Barutello

et al. 2014

BioMed Research International

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The tyrosine kinase human epidermal growth factor receptor 2 (HER2) gene is amplified in approximately 20% of human breast cancers and is associated with an aggressive clinical course and the early development of metastasis. Its crucial role in tumor growth and progression makes HER2 a prototypic oncoantigen, the targeting of which may be critical for the development of effective anticancer therapies. The setup of anti-HER2 targeting strategies has revolutionized the clinical outcome of HER2+ breast cancer. However, their initial success has been overshadowed by the onset of pharmacological resistance that renders them ineffective. Since the tumor microenvironment (TME) plays a crucial role in drug resistance, the design of more effective anticancer therapies should depend on the targeting of both cancer cells and their TME as a whole. In this review, starting from the successful know-how obtained with a HER2+ mouse model of mammary carcinogenesis, the BALB-neuT mice, we discuss the role of TME in mammary tumor development. Indeed, a deeper knowledge of antigens critical for cancer outbreak and progression and of the mechanisms that regulate the interplay between cancer and stromal cell populations could advise promising ways for the development of the best anticancer strategy.

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“…Since breast cancer is a clinically heterogeneous disease, gene-expression signatures of specific subtypes of primary tumors might be a useful prognostic tool to identify the patients with high risk of metastasis. 4,5 PPFIA1 is a gene encoding liprin-α1 in human, which belongs to the liprin family of cytosolic scaffold proteins and includes four liprin-α, two liprin-β members, and liprin-γ/kazrinE. 6 The functions of liprin-α proteins have been mainly studied in neurons, such as regulating active zone morphogenesis, synapse maturation, and trafficking of synaptic vesicles.…”

Section: Introductionmentioning

confidence: 99%

PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse

Yang

Huang

et al. 2017

Tumour Biol.

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Although the oncogenic role of PPFIA1 (liprin-α1) in breast cancer has been reported, whether its dysregulation is associated with metastasis risk or survival outcomes in breast cancer patients is not clear. Our primary data showed that PPFIA1 expression was significantly higher in liver metastatic breast tumors than in the primary tumors. Then, we tried to pool previous annotated genomic data to assess the prognostic value of PPFIA1 in distant metastasis-free survival, the risk of metastatic relapse, and metastatic relapse-free survival in breast cancer patients by data mining in two large databases, Kaplan-Meier plotter and bc-GenExMiner 4.0. Results from Kaplan-Meier plotter showed that although high PPFIA1 expression was generally associated with decreased distant metastasis-free survival in estrogen receptor+ patients, subgroup analysis only confirmed significant association in estrogen receptor+/N− (nodal negative) group (median survival, high PPFIA1 group vs low PPFIA1 cohort: 191.21 vs 236.22 months; hazard ratio: 2.23, 95% confidence interval: 1.42-3.5, p < 0.001), but not in estrogen receptor+/N+ (nodal positive) group (hazard ratio: 1.63, 95% confidence interval: 0.88-3.03, p = 0.12). In estrogen receptor− patients, there was no association between PPFIA1 expression and distant metastasis-free survival, no matter in Nm (nodal status mixed), N−, or N+ subgroups. In bcGenExMiner 4.0, Nottingham Prognostic Index-and Adjuvant! Online-adjusted analysis validated the independent prognostic value of PPFIA1 in metastatic risks in estrogen receptor+/N− patients. Based on these findings, we infer that high PPFIA1 expression might be an independent prognostic indicator of increased metastatic relapse risk in patients with estrogen receptor+/N− breast cancer, but not in estrogen receptor+/N+ or estrogen receptor− patients.

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Clinical and Biological Significance of Hepsin Overexpression in Breast Cancer

Abstract: Our data demonstrate that hepsin expression is frequently up-regulated in breast cancer tissues, which is associated with tumor growth and progression. Thus, inhibition of hepsin expression might be of therapeutic significance.

Cited by 37 publications

References 39 publications

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

Microenvironment, Oncoantigens, and Antitumor Vaccination: Lessons Learned from BALB-neuT Mice

PPFIA1 is upregulated in liver metastasis of breast cancer and is a potential poor prognostic indicator of metastatic relapse

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