All Title Author
Keywords Abstract

PLOS ONE  2014 

Estrogen Regulation of Anti-Apoptotic Bcl-2 Family Member Mcl-1 Expression in Breast Cancer Cells

DOI: 10.1371/journal.pone.0100364

Full-Text   Cite this paper   Add to My Lib


Estrogen is implicated as an important factor in stimulating breast cancer cell proliferation, and presence of estrogen receptor (ER) is an indication of a good prognosis in breast cancer patients. Mcl-1 is an anti-apoptotic Bcl-2 family member that is often over expressed in breast tumors, correlating with poor survival. In breast cancer, it was been previously shown that epidermal growth factor receptors up-regulate Mcl-1 but the role of estrogen in increasing Mcl-1 expression was unknown. In ERα positive cell lines MCF-7 and ZR-75, estrogen treatment increased Mcl-1 expression at both the protein and mRNA level. In two ERα negative cell lines, SK-BR-3 and MDA-MB-231, estrogen failed to increase in Mcl-1 protein expression. We found that ERα antagonists decreased estrogen mediated Mcl-1 expression at both the protein and mRNA level. Upon knockdown of ERα, Mcl-1 mRNA expression after estrogen treatment was also decreased. We also found that ERα binds to the Mcl-1 promoter at a region upstream of the translation start site containing a half ERE site. Streptavidin-pull down assay showed that both ERα and transcription factor Sp1 bind to this region. These results suggest that estrogen is involved in regulating Mcl-1 expression specifically through a mechanism involving ERα.


[1]  Fox EM, Davis RJ, Shupnik MA (2008) ERbeta in breast cancer–onlooker, passive player, or active protector? Steroids 73: 1039–1051. doi: 10.1016/j.steroids.2008.04.006
[2]  Stoica GE, Franke TF, Moroni M, Mueller S, Morgan E, et al. (2003) Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. Oncogene 22: 7998–8011. doi: 10.1038/sj.onc.1206769
[3]  Akgul C (2009) Mcl-1 is a potential therapeutic target in multiple types of cancer. Cell Mol Life Sci 66: 1326–1336. doi: 10.1007/s00018-008-8637-6
[4]  Ding Q, He X, Xia W, Hsu JM, Chen CT, et al. (2007) Myeloid cell leukemia-1 inversely correlates with glycogen synthase kinase-3beta activity and associates with poor prognosis in human breast cancer. Cancer Res 67: 4564–4571. doi: 10.1158/0008-5472.can-06-1788
[5]  Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, et al. (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463: 899–905. doi: 10.1038/nature08822
[6]  Booy EP, Henson ES, Gibson SB (2011) Epidermal growth factor regulates Mcl-1 expression through the MAPK-Elk-1 signalling pathway contributing to cell survival in breast cancer. Oncogene 30: 2367–2378. doi: 10.1038/onc.2010.616
[7]  Henson ES, Hu X, Gibson SB (2006) Herceptin sensitizes ErbB2-overexpressing cells to apoptosis by reducing antiapoptotic Mcl-1 expression. Clin Cancer Res 12: 845–853. doi: 10.1158/1078-0432.ccr-05-0754
[8]  Azijli K, Yuvaraj S, van Roosmalen I, Flach K, Giovannetti E, et al. (2013) MAPK p38 and JNK have opposing activities on TRAIL-induced apoptosis activation in NSCLC H460 cells that involves RIP1 and caspase-8 and is mediated by Mcl-1. Apoptosis 18: 851–860. doi: 10.1007/s10495-013-0829-3
[9]  Boucher MJ, Morisset J, Vachon PH, Reed JC, Laine J, et al. (2000) MEK/ERK signaling pathway regulates the expression of Bcl-2, Bcl-X(L), and Mcl-1 and promotes survival of human pancreatic cancer cells. J Cell Biochem 79: 355–369. doi: 10.1002/1097-4644(20001201)79:3<355::aid-jcb20>;2-s
[10]  Leu CM, Chang C, Hu C (2000) Epidermal growth factor (EGF) suppresses staurosporine-induced apoptosis by inducing mcl-1 via the mitogen-activated protein kinase pathway. Oncogene 19: 1665–1675. doi: 10.1038/sj.onc.1203452
[11]  Becker TM, Boyd SC, Mijatov B, Gowrishankar K, Snoyman S, et al. (2013) Mutant B-RAF-Mcl-1 survival signaling depends on the STAT3 transcription factor. Oncogene doi: 10.1038/onc.2013.45
[12]  Bhattacharya S, Ray RM, Johnson LR (2005) STAT3-mediated transcription of Bcl-2, Mcl-1 and c-IAP2 prevents apoptosis in polyamine-depleted cells. Biochem J 392: 335–344. doi: 10.1042/bj20050465
[13]  Goncharenko-Khaider N, Matte I, Lane D, Rancourt C, Piche A (2012) Ovarian cancer ascites increase Mcl-1 expression in tumor cells through ERK1/2-Elk-1 signaling to attenuate TRAIL-induced apoptosis. Mol Cancer 11: 84. doi: 10.1186/1476-4598-11-84
[14]  Quinn BA, Dash R, Azab B, Sarkar S, Das SK, et al. (2011) Targeting Mcl-1 for the therapy of cancer. Expert Opin Investig Drugs 20: 1397–1411. doi: 10.1517/13543784.2011.609167
[15]  Yang Q, Sakurai T, Jing X, Utsunomiya H, Shan L, et al. (1999) Expression of Bcl-2, but not Bax, correlates with estrogen receptor status and tumor proliferation in invasive breast carcinoma. Pathol Int 49: 775–780. doi: 10.1046/j.1440-1827.1999.00942.x
[16]  Ford D, Easton DF, Stratton M, Narod S, Goldgar D, et al. (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62: 676–689. doi: 10.1086/301749
[17]  Murphy LC, Leygue E (2012) The role of estrogen receptor-beta in breast cancer. Semin Reprod Med 30: 5–13. doi: 10.1055/s-0031-1299592
[18]  Dowsett M, Nicholson RI, Pietras RJ (2005) Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance. Breast Cancer Res Treat 93 Suppl 1: S11–18. doi: 10.1007/s10549-005-9037-3
[19]  Orlando L, Schiavone P, Fedele P, Calvani N, Nacci A, et al. (2010) Molecularly targeted endocrine therapies for breast cancer. Cancer Treat Rev 36 Suppl 3: S67–71. doi: 10.1016/s0305-7372(10)70023-2
[20]  Safe S (2001) Transcriptional activation of genes by 17 beta-estradiol through estrogen receptor-Sp1 interactions. Vitam Horm 62: 231–252. doi: 10.1016/s0083-6729(01)62006-5
[21]  Wu-Peng XS, Pugliese TE, Dickerman HW, Pentecost BT (1992) Delineation of sites mediating estrogen regulation of the rat creatine kinase B gene. Mol Endocrinol 6: 231–240. doi: 10.1210/mend.6.2.1569966
[22]  Dubik D, Shiu RP (1992) Mechanism of estrogen activation of c-myc oncogene expression. Oncogene 7: 1587–1594.
[23]  Porter W, Wang F, Wang W, Duan R, Safe S (1996) Role of estrogen receptor/Sp1 complexes in estrogen-induced heat shock protein 27 gene expression. Mol Endocrinol 10: 1371–1378. doi: 10.1210/mend.10.11.8923463
[24]  Bae J, Leo CP, Hsu SY, Hsueh AJ (2000) MCL-1S, a splicing variant of the antiapoptotic BCL-2 family member MCL-1, encodes a proapoptotic protein possessing only the BH3 domain. J Biol Chem 275: 25255–25261. doi: 10.1074/jbc.m909826199
[25]  Warr MR, Shore GC (2008) Unique biology of Mcl-1: therapeutic opportunities in cancer. Curr Mol Med 8: 138–147. doi: 10.2174/156652408783769580
[26]  Kelly MJ, Levin ER (2001) Rapid actions of plasma membrane estrogen receptors. Trends Endocrinol Metab 12: 152–156. doi: 10.1016/s1043-2760(01)00377-0
[27]  Atanaskova N, Keshamouni VG, Krueger JS, Schwartz JA, Miller F, et al. (2002) MAP kinase/estrogen receptor cross-talk enhances estrogen-mediated signaling and tumor growth but does not confer tamoxifen resistance. Oncogene 21: 4000–4008. doi: 10.1038/sj.onc.1205506
[28]  Britton DJ, Hutcheson IR, Knowlden JM, Barrow D, Giles M, et al. (2006) Bidirectional cross talk between ERalpha and EGFR signalling pathways regulates tamoxifen-resistant growth. Breast Cancer Res Treat 96: 131–146. doi: 10.1007/s10549-005-9070-2
[29]  Kanczuga-Koda L, Koda M, Tomaszewski J, Jarzabek K, Lotowska J, et al. (2010) ERalpha and ERbeta expression in correlation with Ki-67, Bcl-2 and Bak in primary tumors and lymph node metastases of breast cancer: The effect of pre-operative chemotherapy. Oncol Lett 1: 1067–1071. doi: 10.3892/or.18.1.113
[30]  Lewis-Wambi JS, Jordan VC (2009) Estrogen regulation of apoptosis: how can one hormone stimulate and inhibit? Breast Cancer Res 11: 206. doi: 10.1186/bcr2255
[31]  Burow ME, Weldon CB, Tang Y, McLachlan JA, Beckman BS (2001) Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of Bcl-2 by anti-oestrogens. J Steroid Biochem Mol Biol 78: 409–418. doi: 10.1016/s0960-0760(01)00117-0
[32]  Liu W, Swetzig WM, Medisetty R, Das GM (2011) Estrogen-mediated upregulation of Noxa is associated with cell cycle progression in estrogen receptor-positive breast cancer cells. PLoS One 6: e29466. doi: 10.1371/journal.pone.0029466
[33]  Pike CJ (1999) Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. J Neurochem 72: 1552–1563. doi: 10.1046/j.1471-4159.1999.721552.x
[34]  Acoca S, Cui Q, Shore GC, Purisima EO (2011) Molecular dynamics study of small molecule inhibitors of the Bcl-2 family. Proteins 79: 2624–2636. doi: 10.1002/prot.23083
[35]  Kazi A, Sun J, Doi K, Sung SS, Takahashi Y, et al. (2011) The BH3 alpha-helical mimic BH3-M6 disrupts Bcl-X(L), Bcl-2, and MCL-1 protein-protein interactions with Bax, Bak, Bad, or Bim and induces apoptosis in a Bax- and Bim-dependent manner. J Biol Chem 286: 9382–9392. doi: 10.1074/jbc.m110.203638
[36]  Witters LM, Witkoski A, Planas-Silva MD, Berger M, Viallet J, et al. (2007) Synergistic inhibition of breast cancer cell lines with a dual inhibitor of EGFR-HER-2/neu and a Bcl-2 inhibitor. Oncol Rep 17: 465–469. doi: 10.3892/or.17.2.465
[37]  Doi K, Li R, Sung SS, Wu H, Liu Y, et al. (2012) Discovery of marinopyrrole A (maritoclax) as a selective Mcl-1 antagonist that overcomes ABT-737 resistance by binding to and targeting Mcl-1 for proteasomal degradation. J Biol Chem 287: 10224–10235. doi: 10.1074/jbc.m111.334532


comments powered by Disqus