Abstract
IL-34 has been recently identified as a ligand for CSF1R that regulates various cellular processes including cell proliferation, survival, and differentiation. Although the binding of IL-34 to CSF1R modulates several cancer-driving signaling pathways, little is known about the role of IL-34/CSF1R signaling in breast cancer. Herein, we report that IL-34 induces epithelial cell transformation and breast tumorigenesis through activation of MEK/ERK and JNK/c-Jun pathways. IL-34 increased the phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun through CSF1R in mouse skin epidermal JB6 C141 cells and human breast cancer MCF7 cells. IL-34 enhanced c-Fos and c-Jun promoter activity, resulting in increased AP-1 transactivation activity in JB6 Cl41 and MCF7 cells. Moreover, PIN1 enhanced IL-34-induced phosphorylation of MEK1/2, ERK1/2, JNK1/2, and c-Jun in JB6 Cl41 and MCF7 cells. Inhibition of PIN1 using juglone prevented the IL-34-induced transformation of JB6 C141 cells. Similarly, silencing of PIN1 reduced the IL-34-induced tumorigenicity of MCF7 cells. Consistent with these results, the synergistic model showed that treatment with juglone suppressed the IL-34-induced growth of tumors formed by 4T1 cells in BALB/c mice. Our study demonstrates the role of IL-34-induced MEK/ERK and JNK/c-Jun cascades in breast cancer and highlights the regulatory role of PIN1 in IL-34-induced breast tumorigenesis.
Highlights
The tumor microenvironment (TME) has profound influence on tumor cell proliferation, metastasis, and angiogenesis [1]
Inflammatory cells present in the TME release a wide range of soluble signaling molecules known as cytokines, which play an important role in the proliferation, survival, and metastasis of cancer cells [1]
We showed that IL-34 induces neoplastic cellular transformation and breast tumorigenesis through MEK/ERK and JNK/c-Jun signaling pathways
Summary
The tumor microenvironment (TME) has profound influence on tumor cell proliferation, metastasis, and angiogenesis [1]. Immune cells present in the microenvironment, such as macrophages, neutrophils, tumor-infiltrating lymphocytes, and T cells produce a wide range of signaling molecules collectively known as cytokines that play a role in the development and progression of cancers [4]. Interleukins (ILs) are a group of cytokines with complex immunomodulatory functions, including cell proliferation, migration, and adhesion [5]. IL-2, IL-15, and IL-21 are reported to promote tumor suppression in melanoma, whereas IL-1, IL-4, and IL-6 are associated with tumor progression in breast, prostate, and lung cancer [6]. IL-34 has been shown to promote tumor progression and metastasis by recruiting tumor-associated macrophages (TAMs) [8]. The role of IL-34 in breast carcinogenesis is poorly understood
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