Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications

BMC Cancer

Huali Wang¹  Haijing Liu¹  Xin Li¹  Jing Zhao¹  Hong Zhang¹  Jingzhuo Mao¹  Yongxin Zou¹  Hong Zhang²  Shuang Zhang²  Wei Hou¹  Lin Hou¹  Michael A McNutt¹  Bo Zhang¹ 

[1] Department of Pathology, Health Science Center of Peking University, 38 Xueyuan Road, Haidian District, Beijing 100191, China

[2] Department of Pathology, Peking University First Hospital, Beijing 100034, China

关键词: Breast cancer;    Cyclin D1;    p16^INK4a;    Estrogen receptor α;    Bmi1;   

Others  :  859035
DOI  :  10.1186/1471-2407-14-122

 received in 2013-08-07, accepted in 2014-02-19,  发布年份 2014

【 摘 要 】

Background

Bmi1 has been identified as an important regulator in breast cancer, but its relationship with other signaling molecules such as ERα and HER2 is undetermined.

Methods

The expression of Bmi1 and its correlation with ERα, PR, Ki-67, HER2, p16^INK4a, cyclin D1 and pRB was evaluated by immunohistochemistry in a collection of 92 cases of breast cancer and statistically analyzed. Stimulation of Bmi1 expression by ERα or 17β-estradiol (E2) was analyzed in cell lines including MCF-7, MDA-MB-231, ERα-restored MDA-MB-231 and ERα-knockdown MCF-7 cells. Luciferase reporter and chromatin immunoprecipitation assays were also performed.

Results

Immunostaining revealed strong correlation of Bmi1 and ERα expression status in breast cancer. Expression of Bmi1 was stimulated by 17β-estradiol in ERα-positive MCF-7 cells but not in ERα-negative MDA-MB-231 cells, while the expression of Bmi1 did not alter expression of ERα. As expected, stimulation of Bmi1 expression could also be achieved in ERα-restored MDA-MB-231 cells, and at the same time depletion of ERα decreased expression of Bmi1. The proximal promoter region of Bmi1 was transcriptionally activated with co-transfection of ERα in luciferase assays, and the interaction of the Bmi1 promoter with ERα was confirmed by chromatin immunoprecipitation. Moreover, in breast cancer tissues activation of the ERα-coupled Bmi1 pathway generally correlated with high levels of cyclin D1, while loss of its activity resulted in aberrant expression of p16^INK4a and a high Ki-67 index, which implied a more aggressive phenotype of breast cancer.

Conclusions

Expression of Bmi1 is influenced by ERα, and the activity of the ERα-coupled Bmi1 signature impacts p16^INK4a and cyclin D1 status and thus correlates with the tumor molecular subtype and biologic behavior. This demonstrates the important role which is played by ERα-coupled Bmi1 in human breast cancer.

【 授权许可】

   
2014 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Goldhirsch A, Wood W, Coates A, Gelber R, Thürlimann B, Senn HJ: Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen international expert consensus on the primary therapy of early breast cancer 2011. Ann Oncol 2011, 22(8):1736-1747.
• [2]Yamashita H: Current research topics in endocrine therapy for breast cancer. Int J Clin Oncol 2008, 13(5):380-383.
• [3]Musgrove EA, Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 2009, 9(9):631-643.
• [4]Shanle EK, Xu W: Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev 2010, 62(13):1265-1276.
• [5]CTSU RI: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005, 365:1687-1717.
• [6]Singh RR, Kumar R: Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem 2005, 96(3):490-505.
• [7]Medunjanin S, Weinert S, Schmeisser A, Mayer D, Braun-Dullaeus RC: Interaction of the double-strand break repair kinase DNA-PK and estrogen receptor-{alpha}. Mol Biol Cell 2010, 21(9):1620-1628.
• [8]Rodriguez BA, Cheng AS, Yan PS, Potter D, Agosto-Perez FJ, Shapiro CL, Huang TH: Epigenetic repression of the estrogen-regulated Homeobox B13 gene in breast cancer. Carcinogenesis 2008, 29(7):1459-1465.
• [9]Iorns E, Turner NC, Elliott R, Syed N, Garrone O, Gasco M, Tutt AN, Crook T, Lord CJ, Ashworth A: Identification of CDK10 as an important determinant of resistance to endocrine therapy for breast cancer. Cancer Cell 2008, 13(2):91-104.
• [10]Haupt Y, Alexander WS, Barri G, Peter Klinken S, Adams JM: Novel zinc finger gene implicated as myc collaborator by retrovirally accelerated lymphomagenesis in E [mu]-myc transgenic mice. Cell 1991, 65(5):753-763.
• [11]Shao Z, Raible F, Mollaaghababa R, Guyon JR, Wu C, Bender W, Kingston RE: Stabilization of chromatin structure by PRC1, a Polycomb complex. Cell 1999, 98(1):37-46.
• [12]Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y: pRB family proteins are required for H3K27 trimethylation and Polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene. Gene Dev 2007, 21(1):49-54.
• [13]Guo WJ, Datta S, Band V, Dimri GP: Mel-18, a polycomb group protein, regulates cell proliferation and senescence via transcriptional repression of Bmi1 and c-Myc oncoproteins. Mol Biol Cell 2007, 18(2):536-546.
• [14]Liu S, Dontu G, Mantle ID, Patel S, Ahn N, Jackson KW, Suri P, Wicha MS: Hedgehog signaling and Bmi1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006, 66(12):6063-6071.
• [15]Raaphorst FM: Self-renewal of hematopoietic and leukemic stem cells: a central role for the Polycomb-group gene Bmi1. Trends Immunol 2003, 24(10):522-524.
• [16]Vonlanthen S, Heighway J, Altermatt H, Gugger M, Kappeler A, Borner M, van Lohuizen M, Betticher D: The bmi1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 2001, 84(10):1372-1376.
• [17]Silva J, García V, García JM, Peña C, Domínguez G, Díaz R, Lorenzo Y, Hurtado A, Sánchez A, Bonilla F: Circulating Bmi1 mRNA as a possible prognostic factor for advanced breast cancer patients. Breast Cancer Res 2007, 9(4):R55. BioMed Central Full Text
• [18]Engelsen I, Mannelqvist M, Stefansson I, Carter S, Beroukhim R, Øyan A, Otte A, Kalland K, Akslen L, Salvesen H: Low Bmi1 expression is associated with an activated Bmi1-driven signature, vascular invasion, and hormone receptor loss in endometrial carcinoma. Br J Cancer 2008, 98(10):1662-1669.
• [19]Xu Z, Liu H, Lv X, Liu Y, Li S, Li H: Knockdown of the Bmi1 oncogene inhibits cell proliferation and induces cell apoptosis and is involved in the decrease of Akt phosphorylation in the human breast carcinoma cell line MCF-7. Oncol Rep 2011, 25(2):409-418.
• [20]Hoenerhoff MJ, Chu I, Barkan D, Liu ZY, Datta S, Dimri GP, Green JE: Bmi1 cooperates with H-RAS to induce an aggressive breast cancer phenotype with brain metastases. Oncogene 2009, 28(34):3022-3032.
• [21]Pietersen AM, Horlings HM, Hauptmann M, Langerod A, Ajouaou A, Cornelissen-Steijger P, Wessels LF, Jonkers J, van de Vijver MJ, van Lohuizen M: EZH2 and Bmi1 inversely correlate with prognosis and TP53 mutation in breast cancer. Breast Cancer Res 2008, 10(6):R109.
• [22]Guo BH, Feng Y, Zhang R, Xu LH, Li MZ, Kung HF, Song LB, Zeng MS: Bmi1 promotes invasion and metastasis, and its elevated expression is correlated with an advanced stage of breast cancer. Mol Cancer 2011, 10(1):10-33. BioMed Central Full Text
• [23]Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, Fitzgibbons PL, Francis G, Goldstein NS, Hayes M, Hicks DG, Lester S, Love R, Mangu PB, McShane L, Miller K, Osborne CK, Paik S, Perlmutter J, Rhodes A, Sasano H, Schwartz JN, Sweep FC, Taube S, Torlakovic EE, Valenstein P, Viale G, Visscher D, Wheeler T, Williams RB, et al.: American society of clinical oncology/college of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010, 28(16):2784-2795.
• [24]Wolff AC, Hammond MEH, Schwartz JN, Hagerty KL, Allred DC, Cote RJ, Dowsett M, Fitzgibbons PL, Hanna WM, Langer A: American society of clinical oncology/college of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. Arch Pathol Lab Med 2007, 131(1):18-43.
• [25]Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T: Assessment of Ki-67 in breast cancer: recommendations from the international Ki-67 in breast cancer working group. J Natl Cancer Inst 2011, 103(22):1656-1664.
• [26]Essafi A, Gomes AR, Pomeranz KM, Zwolinska AK, Varshochi R, McGovern UB, Lam EW: Studying the subcellular localization and DNA-binding activity of FoxO transcription factors, downstream effectors of PI3K/Akt. Methods Mol Biol 2009, 462:201-211.
• [27]Li SK, Smith DK, Leung WY, Cheung AM, Lam EW, Dimri GP, Yao K-M: FoxM1c counteracts oxidative stress-induced senescence and stimulates Bmi1 expression. J Biol Chem 2008, 283(24):16545-16553.
• [28]Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y: Bmi1 is a target gene for SALL4 in hematopoietic and leukemic cells. Proc Natl Acad Sci USA 2007, 104(25):10494.
• [29]Cicatiello L, Addeo R, Sasso A, Altucci L, Petrizzi VB, Borgo R, Cancemi M, Caporali S, Caristi S, Scafoglio C: Estrogens and progesterone promote persistent CCND1 gene activation during G1 by inducing transcriptional derepression via c-Jun/c-Fos/estrogen receptor (progesterone receptor) complex assembly to a distal regulatory element and recruitment of cyclin D1 to its own gene promoter. Mol Cell Biol 2004, 24(16):7260-7274.
• [30]Sabbah M, Courilleau D, Mester J, Redeuilh G: Estrogen induction of the cyclin D1 promoter: involvement of a cAMP response-like element. Proc Natl Acad Sci USA 1999, 96(20):11217-11222.
• [31]Ochiai H, Takenobu H, Nakagawa A, Yamaguchi Y, Kimura M, Ohira M, Okimoto Y, Fujimura Y, Koseki H, Kohno Y, Nakagawara A, Kamijo T: Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma. Oncogene 2010, 29(18):2681-2690.
• [32]Nowak K, Kerl K, Fehr D, Kramps C, Gessner C, Killmer K, Samans B, Berwanger B, Christiansen H, Lutz W: Bmi1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas. Nucleic Acids Res 2006, 34(6):1745-1754.
• [33]Choi YJ, Choi YL, Cho EY, Shin YK, Sung KW, Hwang YK, Lee SJ, Kong G, Lee JE, Kim JS: Expression of Bmi1 protein in tumor tissues is associated with favorable prognosis in breast cancer patients. Breast Cancer Res Tr 2009, 113(1):83-93.
• [34]Bohn OL, Fuertes-Camilo M, Navarro L, Saldivar J, Sanchez-Sosa S: p16INK4a expression in basal-like breast carcinoma. Int J Clin Exp Pathol 2010, 3(6):600-607.
• [35]da Silveira GG, Oliveira-Costa JP, Soave DF, Zanetti JS, Soares FA, Ribeiro-Silva A: Relationship between B-Cell-specific moloney murine leukemia virus integration site 1 (Bmi1) and homologous recombination regulatory genes in invasive ductal breast carcinomas. Histol Histopathol 2012, 27(10):1353-1359.
• [36]O’Lone R, Frith MC, Karlsson EK, Hansen U: Genomic targets of nuclear estrogen receptors. Mol Endocrinol 2004, 18(8):1859-1875.
• [37]Gruber CJ, Gruber DM, Gruber IM, Wieser F, Huber JC: Anatomy of the estrogen response element. Trends Endocrinol Metab 2004, 15(2):73-78.
• [38]Cicatiello L, Scafoglio C, Altucci L, Cancemi M, Natoli G, Facchiano A, Iazzetti G, Calogero R, Biglia N, de Bortoli M, Sfiligoi C, Sismondi P, Bresciani F, Weisz A: A genomic view of estrogen actions in human breast cancer cells by expression profiling of the hormone-responsive transcriptome. J Mol Endocrinol 2004, 32(3):719-775.
• [39]Dublin EA, Patel NK, Gillett CE, Smith P, Peters G, Barnes DM: Retinoblastoma and p16INK4a proteins in mammary carcinoma: their relationship to cyclin D1 and histopathological parameters. Int J Cancer 1998, 79(1):71-75.
• [40]Arnold A, Papanikolaou A: Cyclin D1 in breast cancer pathogenesis. J Clin Oncol 2005, 23(18):4215-4224.
• [41]Cánepa ET, Scassa ME, Ceruti JM, Marazita MC, Carcagno AL, Sirkin PF, Ogara MF: INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions. IUBMB Life 2007, 59(7):419-426.
• [42]O’Neill CJ, McCluggage WG: p16INK4a expression in the female genital tract and its value in diagnosis. Adv Anat Pathol 2006, 13(1):8-15.
• [43]Kalof AN, Cooper K: p16INK4a immunoexpression: surrogate marker of high-risk HPV and high-grade cervical intraepithelial neoplasia. Adv Anat Pathol 2006, 13(4):190-194.
• [44]Meng S, Luo M, Sun H, Yu X, Shen M, Zhang Q, Zhou R, Ju X, Tao W, Liu D: Identification and characterization of Bmi1-responding element within the human p16INK4a promoter. J Biol Chem 2010, 285(43):33219-33229.
• [45]Pietersen AM, Evers B, Prasad AA, Tanger E, Cornelissen-Steijger P, Jonkers J, van Lohuizen M: Bmi1 regulates stem cells and proliferation and differentiation of committed cells in mammary epithelium. Curr Biol 2008, 18(14):1094-1099.