Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

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

Authors: Huali Wang, Haijing Liu, Xin Li, Jing Zhao, Hong Zhang, Jingzhuo Mao, Yongxin Zou, Hong Zhang, Shuang Zhang, Wei Hou, Lin Hou, Michael A McNutt, Bo Zhang

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

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, p16INK4a, 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 p16INK4a 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 p16INK4a 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.
Appendix
Available only for authorised users
Literature
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. 10.1093/annonc/mdr304.CrossRefPubMedPubMedCentral
2.
Yamashita H: Current research topics in endocrine therapy for breast cancer. Int J Clin Oncol. 2008, 13 (5): 380-383. 10.1007/s10147-008-0818-7.CrossRefPubMed
3.
Musgrove EA, Sutherland RL: Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer. 2009, 9 (9): 631-643. 10.1038/nrc2713.CrossRefPubMed
4.
Shanle EK, Xu W: Selectively targeting estrogen receptors for cancer treatment. Adv Drug Deliv Rev. 2010, 62 (13): 1265-1276. 10.1016/j.addr.2010.08.001.CrossRefPubMedPubMedCentral
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.CrossRef
6.
Singh RR, Kumar R: Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem. 2005, 96 (3): 490-505. 10.1002/jcb.20566.CrossRefPubMed
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. 10.1091/mbc.E09-08-0724.CrossRefPubMedPubMedCentral
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. 10.1093/carcin/bgn115.CrossRefPubMedPubMedCentral
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. 10.1016/j.ccr.2008.01.001.CrossRefPubMed
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. 10.1016/0092-8674(91)90383-A.CrossRefPubMed
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. 10.1016/S0092-8674(00)80604-2.CrossRefPubMed
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. 10.1101/gad.1499407.CrossRefPubMedPubMedCentral
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.CrossRefPubMedPubMedCentral
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. 10.1158/0008-5472.CAN-06-0054.CrossRefPubMedPubMedCentral
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. 10.1016/S1471-4906(03)00241-2.CrossRefPubMed
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. 10.1054/bjoc.2001.1791.CrossRefPubMedPubMedCentral
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): R55-10.1186/bcr1760.CrossRefPubMedPubMedCentral
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. 10.1038/sj.bjc.6604360.CrossRefPubMedPubMedCentral
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.PubMed
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. 10.1038/onc.2009.165.CrossRefPubMedPubMedCentral
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-CrossRefPubMedPubMedCentral
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. 10.1186/1476-4598-10-10.CrossRefPubMedPubMedCentral
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. 10.1200/JCO.2009.25.6529.CrossRefPubMedPubMedCentral
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.PubMed
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. 10.1093/jnci/djr393.CrossRefPubMedPubMedCentral
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.PubMed
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. 10.1074/jbc.M709604200.CrossRefPubMedPubMedCentral
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): 10494-10.1073/pnas.0704001104.CrossRefPubMedPubMedCentral
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. 10.1128/MCB.24.16.7260-7274.2004.CrossRefPubMedPubMedCentral
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. 10.1073/pnas.96.20.11217.CrossRefPubMedPubMedCentral
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. 10.1038/onc.2010.22.CrossRefPubMed
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. 10.1093/nar/gkl119.CrossRefPubMedPubMedCentral
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. 10.1007/s10549-008-9909-4.CrossRef
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.PubMedPubMedCentral
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.PubMed
36.
O’Lone R, Frith MC, Karlsson EK, Hansen U: Genomic targets of nuclear estrogen receptors. Mol Endocrinol. 2004, 18 (8): 1859-1875. 10.1210/me.2003-0044.CrossRefPubMed
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. 10.1016/j.tem.2004.01.008.CrossRefPubMed
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. 10.1677/jme.0.0320719.CrossRefPubMed
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. 10.1002/(SICI)1097-0215(19980220)79:1<71::AID-IJC14>3.0.CO;2-K.CrossRefPubMed
40.
Arnold A, Papanikolaou A: Cyclin D1 in breast cancer pathogenesis. J Clin Oncol. 2005, 23 (18): 4215-4224. 10.1200/JCO.2005.05.064.CrossRefPubMed
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. 10.1080/15216540701488358.CrossRefPubMed
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. 10.1097/01.pap.0000201828.92719.f3.CrossRefPubMed
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. 10.1097/00125480-200607000-00006.CrossRefPubMed
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. 10.1074/jbc.M110.133686.CrossRefPubMedPubMedCentral
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. 10.1016/j.cub.2008.06.070.CrossRefPubMed
Metadata
Title
Estrogen receptor α-coupled Bmi1 regulation pathway in breast cancer and its clinical implications
Authors
Huali Wang
Haijing Liu
Xin Li
Jing Zhao
Hong Zhang
Jingzhuo Mao
Yongxin Zou
Hong Zhang
Shuang Zhang
Wei Hou
Lin Hou
Michael A McNutt
Bo Zhang
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-122

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

The saga of the many studies wrongly associating mitochondrial DNA with breast cancer

Research article

The Rho-kinase inhibitor HA-1077 suppresses proliferation/migration and induces apoptosis of urothelial cancer cells

Study protocol

Rationale and design of LUX-Head & Neck 1: a randomised, Phase III trial of afatinib versus methotrexate in patients with recurrent and/or metastatic head and neck squamous cell carcinoma who progressed after platinum-based therapy

Study protocol

Correlating tumor metabolic progression index measured by serial FDG PET-CT, apparent diffusion coefficient measured by magnetic resonance imaging (MRI) and blood genomics to patient’s outcome in advanced colorectal cancer: the CORIOLAN study

Research article

Elevated preoperative peripheral blood monocyte count predicts poor prognosis for hepatocellular carcinoma after curative resection

Research article

The cost of lost productivity due to premature cancer-related mortality: an economic measure of the cancer burden
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits