title: MEK activity controls IL-8 expression in tamoxifen-resistant MCF-7 breast cancer cells.
abstract: Although tamoxifen reduces disease progression, tamoxifen resistance occurs during the course of estrogen receptor-positive [ER+] breast cancer treatment. In the present study, we investigated the possibility that interleukin-8 (IL-8) is a prognostic marker for tamoxifen resistance and aimed to clarify the regulation of IL-8 expression in tamoxifen-resistant cells. Clinically, IL-8 expression is positively correlated with survival in luminal A type breast cancer patients, but not in luminal B type breast cancer patients. In addition, the levels of IL-8 mRNA and protein expression were significantly increased in tamoxifen-resistant (TamR) cells compared to tamoxifen-sensitive (TamS) cells. To determine the regulatory mechanism of IL-8 expression in TamR cells, we analyzed the activities of signaling molecules. Our results showed that the phosphorylation levels of MEK and Akt were markedly increased in TamR cells, but there was no change in the phosphorylation level of p38 MAPK. On the contrary, we observed that elevated IL-8 mRNA expression was suppressed by a specific MEK1/2 inhibitor, UO126, but not by the specific PI-3K inhibitor LY294002, in TamR cells, whereas, we found that overexpression of constitutively active-MEK (CA-MEK) significantly increased the levels of IL-8 mRNA expression in TamS cells. Finally, we investigated the effect of the specific CXCR1/2 inhibitor SB225002 on anchorage-independent growth of TamR cells, and found that the growth was completely suppressed by SB225002. Taken together, our results demonstrate that IL-8 expression is regulated through a MEK/ERK-dependent pathway in TamR cells, suggesting that IL-8 and its receptors may be promising therapeutic targets for overcoming tamoxifen resistance.
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Sangmin
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Myeongjin
authors.initials: M
authors.lastname: Jeon
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Jeong Eon
authors.initials: JE
authors.lastname: Lee
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Gangnam-gu, Seoul 135-710, Republic of Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Nam
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D010766:Phosphorylation / Q000187:drug effects; D013629:Tamoxifen / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D018931:Antineoplastic Agents, Hormonal; C508606:CXCL8 protein, human; D016209:Interleukin-8; D013629:Tamoxifen