Abstract
Estrogen receptor (ER) α is essential for estrogen-dependent growth, and its level of expression is a crucial determinant of response to endocrine therapy and prognosis in ERα-positive breast cancer. Breast cancer patients show a wide range of ERα expression levels and the levels of expression in individual patients change during disease progression and in response to systemic therapies. However, little is known about how the expression of ERα in human breast cancer is regulated. Recently, several microRNAs (miRNAs) that directly target ERα have been identified, and we previously demonstrated that miR-206 expression was downregulated in ERα-positive human breast cancer. In this study, expression levels of miRNAs that directly target ERα, including miR-18a, miR-18b, miR-22, miR-193b, miR-221/222 and miR-302c, were analyzed in human breast cancer samples by quantitative reverse transcription-PCR analysis. Correlations between the expression levels of these miRNAs and clinicopathological factors, including prognosis, were analyzed. miR-18a expression was much higher in ERα-negative than in ERα-positive tumors (P < 0.0001), with the expression levels of miR-18a not differing in ERα-positive breast cancer as a function of ERα protein level. Surprisingly, the expression levels of miR-193b and miR-221 were significantly lower in ERα-negative than in ERα-positive tumors (P = 0.0015 and P = 0.0045, respectively), and the levels of these miRNAs gradually increased as ERα protein expression increased. There was no statistically significant association between miR-22 and ERα expression, and miR-302c expression was minimal in human breast cancer samples. Prognostic analysis showed that low miR-18b expression was significantly associated with improved survival in HER2-negative breast cancer, although miR-18b expression was not correlated with ERα protein expression. Our results suggest that miRNAs that directly target ERα have distinct roles in not only regulating ERα but also regulating other target genes in human breast cancer.
References
Harvey JM, Clark GM, Osborne CK, Allred DC (1999) Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 17:1474–1481
Yamashita H, Ando Y, Nishio M, Zhang Z, Hamaguchi M, Mita K, Kobayashi S, Fujii Y, Iwase H (2006) Immunohistochemical evaluation of hormone receptor status for predicting response to endocrine therapy in metastatic breast cancer. Breast Cancer 13:74–83
Dowsett M, Allred C, Knox J, Quinn E, Salter J, Wale C, Cuzick J, Houghton J, Williams N, Mallon E, Bishop H, Ellis I, Larsimont D, Sasano H, Carder P, Cussac AL, Knox F, Speirs V, Forbes J, Buzdar A (2008) Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. J Clin Oncol 26:1059–1065
Herynk MH, Fuqua SA (2004) Estrogen receptor mutations in human disease. Endocr Rev 25:869–898
Giacinti L, Claudio PP, Lopez M, Giordano A (2006) Epigenetic information and estrogen receptor alpha expression in breast cancer. Oncologist 11:1–8
Holst F, Stahl PR, Ruiz C, Hellwinkel O, Jehan Z, Wendland M, Lebeau A, Terracciano L, Al-Kuraya K, Janicke F, Sauter G, Simon R (2007) Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet 39:655–660
Yamashita H, Iwase H, Toyama T, Takahashi S, Sugiura H, Yoshimoto N, Endo Y, Fujii Y, Kobayashi S (2011) Estrogen receptor-positive breast cancer in Japanese women: trends in incidence, characteristics, and prognosis. Ann Oncol 22:1318–1325
Yamashita H, Takahashi S, Ito Y, Yamashita T, Ando Y, Toyama T, Sugiura H, Yoshimoto N, Kobayashi S, Fujii Y, Iwase H (2009) Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer. Cancer Sci 100:2028–2033
Kondo N, Toyama T, Sugiura H, Fujii Y, Yamashita H (2008) miR-206 Expression is down-regulated in estrogen receptor alpha-positive human breast cancer. Cancer Res 68:5004–5008
Krol J, Loedige I, Filipowicz W (2010) The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet 11:597–610
Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269
Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Menard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070
Blenkiron C, Goldstein LD, Thorne NP, Spiteri I, Chin SF, Dunning MJ, Barbosa-Morais NL, Teschendorff AE, Green AR, Ellis IO, Tavare S, Caldas C, Miska EA (2007) MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol 8:R214
Adams BD, Furneaux H, White BA (2007) The micro-ribonucleic acid (miRNA) miR-206 targets the human estrogen receptor-alpha (ERalpha) and represses ERalpha messenger RNA and protein expression in breast cancer cell lines. Mol Endocrinol 21:1132–1147
Adams BD, Cowee DM, White BA (2009) The role of miR-206 in the epidermal growth factor (EGF) induced repression of estrogen receptor-alpha (ERalpha) signaling and a luminal phenotype in MCF-7 breast cancer cells. Mol Endocrinol 23:1215–1230
Leivonen SK, Makela R, Ostling P, Kohonen P, Haapa-Paananen S, Kleivi K, Enerly E, Aakula A, Hellstrom K, Sahlberg N, Kristensen VN, Borresen-Dale AL, Saviranta P, Perala M, Kallioniemi O (2009) Protein lysate microarray analysis to identify microRNAs regulating estrogen receptor signaling in breast cancer cell lines. Oncogene 28:3926–3936
Pandey DP, Picard D (2009) miR-22 inhibits estrogen signaling by directly targeting the estrogen receptor alpha mRNA. Mol Cell Biol 29:3783–3790
Xiong J, Yu D, Wei N, Fu H, Cai T, Huang Y, Wu C, Zheng X, Du Q, Lin D, Liang Z (2010) An estrogen receptor alpha suppressor, microRNA-22, is downregulated in estrogen receptor alpha-positive human breast cancer cell lines and clinical samples. FEBS J 277:1684–1694
Zhao JJ, Lin J, Yang H, Kong W, He L, Ma X, Coppola D, Cheng JQ (2008) MicroRNA-221/222 negatively regulates estrogen receptor alpha and is associated with tamoxifen resistance in breast cancer. J Biol Chem 283:31079–31086
Di Leva G, Gasparini P, Piovan C, Ngankeu A, Garofalo M, Taccioli C, Iorio MV, Li M, Volinia S, Alder H, Nakamura T, Nuovo G, Liu Y, Nephew KP, Croce CM (2010) MicroRNA cluster 221–222 and estrogen receptor alpha interactions in breast cancer. J Natl Cancer Inst 102:706–721
Yamashita H, Nishio M, Toyama T, Sugiura H, Kondo N, Kobayashi S, Fujii Y, Iwase H (2008) Low phosphorylation of estrogen receptor alpha (ERalpha) serine 118 and high phosphorylation of ERalpha serine 167 improve survival in ER-positive breast cancer. Endocr Relat Cancer 15:755–763
Allred DC, Harvey JM, Berardo M, Clark GM (1998) Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 11:155–168
Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P, Barton G, Jiao LR, Wait R, Waxman J, Hannon GJ, Stebbing J (2009) The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci USA 106:15732–15737
Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, Jacob S, Majumder S (2008) MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem 283:29897–29903
Kedde M, van Kouwenhove M, Zwart W, Oude Vrielink JA, Elkon R, Agami R (2010) A Pumilio-induced RNA structure switch in p27–3’ UTR controls miR-221 and miR-222 accessibility. Nat Cell Biol 12:1014–1020
Li XF, Yan PJ, Shao ZM (2009) Downregulation of miR-193b contributes to enhance urokinase-type plasminogen activator (uPA) expression and tumor progression and invasion in human breast cancer. Oncogene 28:3937–3948
Sliva D, Rizzo MT, English D (2002) Phosphatidylinositol 3-kinase and NF-kappaB regulate motility of invasive MDA-MB-231 human breast cancer cells by the secretion of urokinase-type plasminogen activator. J Biol Chem 277:3150–3157
Pakneshan P, Szyf M, Farias-Eisner R, Rabbani SA (2004) Reversal of the hypomethylation status of urokinase (uPA) promoter blocks breast cancer growth and metastasis. J Biol Chem 279:31735–31744
Pakneshan P, Tetu B, Rabbani SA (2004) Demethylation of urokinase promoter as a prognostic marker in patients with breast carcinoma. Clin Cancer Res 10:3035–3041
Pulukuri SM, Rao JS (2007) Small interfering RNA directed reversal of urokinase plasminogen activator demethylation inhibits prostate tumor growth and metastasis. Cancer Res 67:6637–6646
Wu W, Lin Z, Zhuang Z, Liang X (2009) Expression profile of mammalian microRNAs in endometrioid adenocarcinoma. Eur J Cancer Prev 18:50–55
Rauhala HE, Jalava SE, Isotalo J, Bracken H, Lehmusvaara S, Tammela TL, Oja H, Visakorpi T (2010) miR-193b is an epigenetically regulated putative tumor suppressor in prostate cancer. Int J Cancer 127:1363–1372
Xu C, Liu S, Fu H, Li S, Tie Y, Zhu J, Xing R, Jin Y, Sun Z, Zheng X (2010) MicroRNA-193b regulates proliferation, migration and invasion in human hepatocellular carcinoma cells. Eur J Cancer 46:2828–2836
Chen J, Feilotter HE, Pare GC, Zhang X, Pemberton JG, Garady C, Lai D, Yang X, Tron VA (2010) MicroRNA-193b represses cell proliferation and regulates cyclin D1 in melanoma. Am J Pathol 176:2520–2529
Guo J, Miao Y, Xiao B, Huan R, Jiang Z, Meng D, Wang Y (2009) Differential expression of microRNA species in human gastric cancer versus non-tumorous tissues. J Gastroenterol Hepatol 24:652–657
Tatsuguchi M, Seok HY, Callis TE, Thomson JM, Chen JF, Newman M, Rojas M, Hammond SM, Wang DZ (2007) Expression of microRNAs is dynamically regulated during cardiomyocyte hypertrophy. J Mol Cell Cardiol 42:1137–1141
Otaegui D, Baranzini SE, Armananzas R, Calvo B, Munoz-Culla M, Khankhanian P, Inza I, Lozano JA, Castillo-Trivino T, Asensio A, Olaskoaga J, Lopez de Munain A (2009) Differential micro RNA expression in PBMC from multiple sclerosis patients. PLoS One 4:e6309
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This work was supported in part by Grant-in Aid for Scientific Research from Japan Society for the Promotion of Science.
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Yoshimoto, N., Toyama, T., Takahashi, S. et al. Distinct expressions of microRNAs that directly target estrogen receptor α in human breast cancer. Breast Cancer Res Treat 130, 331–339 (2011). https://doi.org/10.1007/s10549-011-1672-2
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DOI: https://doi.org/10.1007/s10549-011-1672-2