Loss of Proprotein Convertase Furin in Mammary Gland Impairs proIGF1R and proIR Processing and Suppresses Tumorigenesis in Triple Negative Breast Cancer.

Zongsheng He,John W M Creemers,Abdel-Majid Khatib

doi:10.3390/cancers12092686

Zongsheng He, John W M Creemers + Show 1 more

Open Access

https://doi.org/10.3390/cancers12092686

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Journal: Cancers	Publication Date: Sep 20, 2020
Citations: 16	License type: CC BY 4.0

Affiliation: KU Leuven, Inserm, Institut Bergonié

Abstract

Simple SummaryTriple-negative breast cancer (TNBC) is known to have a poor prognosis and limited treatment options. The aim of the current study is to evaluate the role of Furin, a proprotein convertase involved in the activation of wide range of protein precursors in TNBC progression. The generation of a TNBC mouse model lacking Furin specifically in the mammary gland confirmed that Furin is implicated in TNBC tumor progression and the derived lung metastasis. Further analysis revealed that the proteolytic activation of proIGF1R and proIR receptors, two substrates of Furin involved in TNBC were inhibited in these mice and was associated with reduced AKT and ERK1/2 expression and phosphorylation. In addition, Furin is frequently overexpressed in TNBC tumors and correlates with poor patient prognosis, suggesting the use of Furin inhibition as a potential adjunct therapy in TNBC.In triple negative breast cancer (TNBC) cell lines, the proprotein convertase Furin cleaves and then activates several protein precursors involved in oncogenesis. However, the in vivo role of Furin in the mammary gland and how mammary gland-specific Furin knockout specifically influences tumor initiation and progression of TNBC is unknown. Here, we report that Furin is frequently overexpressed in TNBC tumors and this correlates with poor prognosis in patients with TNBC tumors. In a whey acidic protein (WAP)-induced mammary epithelial cell-specific Furin knockout mouse model, mice show normal mammary development. However, loss of Furin in mammary glands inhibits primary tumor growth and lung metastasis in an oncogene-induced TNBC mouse model. Further analysis of TNBC mice lacking Furin revealed repressed maturation of the Furin substrates proIGF1R and proIR that are associated with reduced expression and activation of their downstream effectors PI3K/AKT and MAPK/ERK1/2. In addition, these tissues showed enhanced apoptotic signaling. In conclusion, our findings reveal that upregulated Furin expression reflects the poor prognosis of TNBC patients and highlights the therapeutic potential of inhibiting Furin in TNBC tumors.

Highlights

Breast cancer is a heterogeneous disease with variable histological characteristics, clinical outcomes and treatment responses
To identify whether Furin expression is deregulated during breast carcinogenesis, we analyzed the mRNA expression of Furin in human breast cancer tissues and normal breast tissues using the Gent2 online tool [26]
triple-negative breast cancer (TNBC) tumor tissues showed higher expression levels of Furin compared to other subtypes including human epidermal growth factor receptor 2 (HER2), Luminal A and Luminal B (Figure 1B), indicating that upregulated Furin expression plays a more important role in TNBC compared to the other three subtypes

Summary

Introduction

Breast cancer is a heterogeneous disease with variable histological characteristics, clinical outcomes and treatment responses. Many other Furin substrates like IGF1R [9,10] and c-MET [11,12] have been reported to maintain the tumorigenic properties of TNBC cells. Inhibition of IGF1R represses tumor growth and induces apoptosis in different TNBC cell lines [13]. Other studies have reported that well-established Furin substrates, including NOTCH1 [11,16] and TGFβ1 [11,17], influence the oncogenic capabilities of TNBC cells [18,19]. These studies indicate that Furin plays an important role in TNBC

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