Furin, one of the members of the family of
proprotein convertases (PCs), ubiquitously expressed as a type I membrane-bound
proteinase, activates several
proteins that contribute to
tumor progression. In vitro studies using
cancer cell lines and clinical specimens demonstrated that
furin processes important substrates such as
insulin-like growth factor 1 receptor (IGF-1R) and
transforming growth factor β, leading to increased
tumor growth and progression. Despite the numerous studies associating
furin with
tumor development, its effects in preclinical models has not been comprehensively studied. In this study, we sought to determine the protumorigenic role of
furin in vivo after a two-stage chemical
carcinogenesis protocol in transgenic mice in which
furin expression was targeted to the epidermal basal layer. We found that processing of the PC substrate IGF-1R and the proliferation rate of mouse epidermis was enhanced in transgenic mice when compared with their WT counterparts. Histopathologic diagnoses of the
tumors demonstrated that
furin transgenic mice (line F47) developed twice as many
squamous carcinomas as the control, WT mice (P < .002). Similarly,
tumors cells from transgenic mice were able to process PC substrates more efficiently than
tumor cells from WT mice. Furthermore,
furin expression resulted in a higher SCC volume in transgenic mice as well as an increase in the percentage of high-grade SCC, including poorly differentiated and
spindle cell carcinomas. In conclusion, expression of
furin in the basal layer of the epidermis increased
tumor development and enhanced
tumor growth, supporting the consideration of
furin as a potential target for
cancer treatment.