MEK-dependent IL-8 induction regulates the invasiveness of triple-negative breast cancer cells
Interleukin-8 (IL-8) serves as a prognostic marker for breast cancer, and its expression level correlates with metastatic breast cancer and poor prognosis. Here, we investigated the levels of IL-8 expression in a variety of breast cancer cells and the regulatory mechanism of IL-8 in triple-negative breast cancer (TNBC) cells. Our results showed that IL-8 expression correlated positively with overall survival in basal-type breast cancer patients. The levels of IL-8 mRNA expression and protein secretion were significantly increased in TNBC cells compared with non-TNBC cells. In addition, the invasiveness of the TNBC cells was dramatically increased by IL-8 treatment and then augmented invasion-related proteins such as matrix metalloproteinase (MMP)-2 or MMP-9. We observed that elevated IL-8 mRNA expression and protein secretion were suppressed by a specific MEK1/2 inhibitor, UO126. In contrast, the overexpression of constitutively active MEK significantly increased the level of IL-8 mRNA expression in BT474 non-TNBC cells. Finally, we investigated the effect of UO126 on the tumorigenecity of TNBC cells. Our results showed that anchorage-independent growth, cell invasion, and cell migration were also decreased by UO126 in TNBC cells. As such, we demonstrated that IL-8 expression is regulated through MEK/ERK-dependent pathways in TNBC cells. A diversity of MEK blockers, including UO126, may be promising for treating TNBC patients.
KeywordsIL-8 Poor prognosis Cell invasion MEK Triple-negative breast cancer
This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) and funded by the Ministry of Health & Welfare, Republic of Korea (HI14C3418), and by a Samsung Biomedical Research Institute grant (SMX1131701).
Compliance with ethical standards
Conflicts of interest
- 12.Baud V, Liu ZG, Bennett B, Suzuki N, Xia Y, Karin M. Signaling by proinflammatory cytokines: oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Dev. 1999;13:1297–308.CrossRefPubMedPubMedCentralGoogle Scholar
- 16.Krzystek-Korpacka M, Matusiewicz M, Diakowska D, Grabowski K, Blachut K, Konieczny D, et al. Elevation of circulating interleukin-8 is related to lymph node and distant metastases in esophageal squamous cell carcinomas—implication for clinical evaluation of cancer patient. Cytokine+. 2008;41:232–9. doi: 10.1016/j.cyto.2007.11.011.PubMedGoogle Scholar
- 17.Hartman ZC, Poage GM, den Hollander P, Tsimelzon A, Hill J, Panupinthu N, et al. Growth of triple-negative breast cancer cells relies upon coordinate autocrine expression of the proinflammatory cytokines IL-6 and IL-8. Cancer Res. 2013;73:3470–80. doi: 10.1158/0008-5472.CAN-12-4524-T.CrossRefPubMedGoogle Scholar
- 19.Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31. doi: 10.1007/s10549-009-0674-9.CrossRefPubMedGoogle Scholar
- 20.Benoy IH, Salgado R, Van Dam P, Geboers K, Van Marck E, Scharpe S, et al. Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival. Clin Cancer Res. 2004;10:7157–62. doi: 10.1158/1078-0432.CCR-04-0812.CrossRefPubMedGoogle Scholar