Upregulated IL-19 in Breast Cancer Promotes Tumor Progression and Affects Clinical Outcome

• Published in: Clinical cancer research 2012-02, Vol.18 (3), p.713-725
• Main Authors: HSING, Chung-Hsi, CHENG, Hung-Chi, HSU, Yu-Hsiang, CHAN, Chien-Hui, YEH, Ching-Hua, LI, Chien-Feng, CHANG, Ming-Shi
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Biomarkers, Tumor - analysis; Blotting, Western; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Carcinoma, Ductal, Breast - metabolism; Carcinoma, Ductal, Breast - mortality; Carcinoma, Ductal, Breast - pathology; Cell Line, Tumor; Cell Separation; Disease Progression; Female; Flow Cytometry; Gene Knockdown Techniques; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Interleukin-10 - biosynthesis; Interleukins - biosynthesis; Kaplan-Meier Estimate; Mammary gland diseases; Medical sciences; Mice; Mice, Inbred BALB C; Middle Aged; Neoplasm Staging; Pharmacology. Drug treatments; Prognosis; Real-Time Polymerase Chain Reaction; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Treatment Outcome; Tumors; Up-Regulation
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-1532

Interleukin (IL)-19 was expressed in invasive ductal carcinoma (IDC) of the breast tissue but not in healthy breast tissue. We explored the effects of IL-19 on the pathogenesis of breast cancer and its clinical outcome. Tumor expression of IL-19 was assessed by immunohistochemistry and/or real-time quantitative PCR between two groups of patients with breast IDC (n = 60 and 143, respectively) with available clinical and survival data. We examined the effects of IL-19 on cytokine and chemokine production as well as proliferation and migration in breast cancer cells. Mice were injected with IL-19-overexpressing or vector control 67NR cells and the tumor growth and lung metastatic micronodules were measured. Of the IDC specimens, high IL-19 expression was associated with advanced tumor stage, high tumor metastasis, and worse survival. In vitro, IL-19 induced transcripts of IL-1β, IL-6, TGF-β, matrix metalloproteinase (MMP)2, MMP9, and CXCR4 in 4T1 breast cancer cells; induced fibronectin expression and assembly; and promoted cancer cell proliferation and migration, which were inhibited by anti-IL-19 monoclonal antibody (mAb). Endogenous fibronectin expression and cancer cell migration were lower in IL-19 knockdown 4T1 cells. In 4T1 cells, hypoxia induced IL-19 and CXCR4 expression, which was inhibited by anti-IL-19 mAb. IL-19 overexpression in noninvasive 67NR cancer cells increased cell proliferation and migration. In vivo, mice injected with IL-19-overexpressing 67NR cell clones showed larger tumors and more metastatic micronodules in the lung. High IL-19 expression in breast cancer tissue is associated with a poor clinical outcome. IL-19 is pivotal in the pathogenesis of breast cancer.