A homeobox protein, NKX6.1, up-regulates interleukin-6 expression for cell growth in basal-like breast cancer cells

• Published in: Experimental cell research 2016-05, Vol.343 (2), p.177-189
• Main Authors: Li, Wenzhao, Itou, Junji, Tanaka, Sunao, Nishimura, Tomomi, Sato, Fumiaki, Toi, Masakazu
• Format: Article
• Language: English
• Subjects: Animals; Basal-like breast cancer; Base Sequence; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer therapies; Carcinogenesis - pathology; Cell growth; Cell Line, Tumor; Cell Proliferation; Cellular biology; Feedback, Physiological; Female; Gene Expression Regulation, Neoplastic; Homeodomain Proteins - metabolism; Humans; IL-6; Interleukin-6 - genetics; Interleukin-6 - metabolism; Mice, Inbred NOD; Mice, SCID; Models, Biological; NKX6.1; Promoter Regions, Genetic; Proteins; Transcription factor; Up-Regulation - genetics
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2016.03.023

Among breast cancer subtypes, basal-like breast cancer is particularly aggressive, and research on the molecules involved in its pathology might contribute to therapy. In this study, we found that expression of NKX6.1, a homeobox transcription factor, is higher in basal-like breast cancer than in other subtypes. In loss-of-function experiments on basal-like breast cancer cell lines, NKX6.1-depleted cells exhibited reduced cell growth. Because cytokine interleukin-6 (IL-6) is expressed in basal-like breast cancer, and increases cell growth, we analyzed expression levels of IL6, an IL-6 gene, and observed reduced IL6 expression in NKX6.1-depleted cells. In a reporter assay, IL6 promoter activity was reduced by loss of NKX6.1 function. A pull-down assay showed that NKX6.1 binds to the proximal region in IL6 promoter. These results indicate that NKX6.1 directly up-regulates IL6 expression. To investigate further, we established cells with forced expression of IL-6. We observed that exogenous IL-6 expression restored the reduced cell growth of NKX6.1-depleted cells. Furthermore, orthotopic xenografts showed that NKX6.1-depleted cells lost the capacity for tumor formation. We therefore conclude that NKX6.1 is a factor for IL-6-regulated growth and tumor formation in basal-like breast cancer. Our findings facilitate profound understanding of basal-like breast cancer, and the development of suitable therapy. •NKX6.1 is up-regulated in basal-like breast cancer.•NKX6.1 directly promotes IL6 expression.•The NKX6.1-IL-6 network positively regulates cell growth.•NKX6.1 is involved in tumor formation.