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

Abstract

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.

Keywords

• triple negative breast cancer
• Furin
• AKT
• ERK1/2