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Horm Metab Res 2007; 39(4): 288-294
DOI: 10.1055/s-2007-973814
Original Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Sex Hormone-binding Globulin Selectively Modulates Estradiol-regulated Genes in MCF-7 Cells

M. G. Catalano 1 , L. Costantino 1 , R. Frairia 1 , G. Boccuzzi 1 , 2 , N. Fortunati 2
  • 1Department of Clinical Physiopathology, University of Turin, Turin, Italy
  • 2Oncological Endocrinology, ASO San Giovanni Battista, Turin, Italy
Further Information

Publication History

received 28. 7. 2006

accepted 27. 11. 2006

Publication Date:
19 April 2007 (online)

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Abstract

Human sex hormone-binding globulin inhi-bits the effects of estradiol on proliferation and apoptosis of breast cancer cells. We report here the effect of sex hormone-binding globulin on estradiol regulation of gene expression in MCF-7 breast cancer cells using a selected set of genes. Estradiol upregulates genes that are positive regulators of proliferation (e.g., bcl-2, c-fos, c-myc, cyclin D) or/and related to more aggressive form of breast cancer (e.g. BRCA-1, EGF-R) and downregulates two genes (c-jun and ERα). Sex hormone-binding globulin modulates only a selected group of estradiol-controlled genes (inhibiting upregulation of bcl-2, c-myc, EGF-R, PR, and downregulation of ERα), starting 48 hours after treatment. Our study demonstrates that in breast cancer cells, sex hormone-binding globulin is effective on few selected genes which are involved in cell growth and apoptosis or related to cell estrogen-dependence and that the protein regulation of estradiol effect is selected and specific. Sex hormone-binding globulin action in estrogen breast cancer cells is strongly associated to cell growth and estrogen-sensitivity.

Key words

SHBG - estradiol - gene expression - breast cancer

References

  • 1 Dickson RB, Thompson EW, Lippman ME. Hormones and breast cancer in vitro.  Hum Cell. 1989;  2 219-230
    PubMedGoogle Scholar
  • 2 Russo IH, Russo J. Role of hormones in mammary cancer initiation and progression.  J. Mammary Gland Biol Neoplasia. 1998;  3 49-61
    CrossrefPubMedGoogle Scholar
  • 3 van de Vijver MJ, He YD, van't Veer LJ, Dai H, Hart AA, Voskuil DW, Schreber GJ, Peterse JL, Roberts C, Marton MJ, Parrish M, Atsma D, Witteven A, Glas A, Delahaye L, van der Velde T, Baterlink H, Rodenhuis S, Rutgers ET, Friend SH, Bernards R. A gene expression signature as a predictor of survival in breast cancer.  N Engl J Med. 2002;  347 1999-2009
    CrossrefPubMedGoogle Scholar
  • 4 van't Veer LJ, Dai H, van de Vijver MJ, He YD, Hart AA, Mao M, Peterse JL, van der Kooy K, Marton MJ, Witteveen AT, Schreiber GJ, Kerkhoven RM, Roberts C, Linsley PS, Bernards R, Friend SH. Gene expression profiling predicts clinical outcome of breast cancer.  Nature. 2002;  415 530-536
    CrossrefPubMedGoogle Scholar
  • 5 Sotiriou C, Powles TJ, Dowsett M, Jazaeri AA, Feldman AL, Assersohn L, Galdisetti C, Libutti SK, Liu ET. Gene expression profiles derived from fine needle aspiration correlate with response to systemic chemotherapy in breast cancer.  Breast Cancer Res. 2002;  4 R3
    CrossrefPubMedGoogle Scholar
  • 6 Frasor J, Danes JM, Komm B, Chang KCN, Lyttle R, Katzenellenbogen BS. Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype.  Endocrinology. 2003;  144 4562-4574
    CrossrefPubMedGoogle Scholar
  • 7 Hammond GL, Avvakumov GV, Muller YA. Structure/function analyses of human sex hormone-binding globulin: effects of zinc on steroid-binding specificity.  J Steroid Biochem Mol Biol. 2003;  85 195-200
    CrossrefPubMedGoogle Scholar
  • 8 Caldwell JD, Suleman F, Chou SH, Shapiro RA, Herbert Z, Jirikowski GF. Emerging roles of steroid-binding globulins.  Horm Metab Res. 2006;  38 206-218
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Fortunati N, Catalano MG. Sex hormone-binding globulin (SHBG) and estradiol cross-talk in breast cancer cells.  Horm Metab Res. 2006;  38 236-240
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Porto CS, Musto NA, Bardin CW, Gunsalus GL. Binding of an extracellular steroid-binding globulin to membranes and soluble receptors from human breast cancer cells (MCF-7 cells).  Endocrinology. 1992;  130 2931-2936
    CrossrefPubMedGoogle Scholar
  • 11 Fortunati N, Fissore F, Fazzari A, Berta L, Benedusi-Pagliano E, Frairia R. Biological relevance of the interaction between sex steroid binding protein and its specific receptor of MCF-7 cells: effect on the estradiol-induced cell proliferation.  J Steroid Biochem Mol Biol. 1993;  45 435-444
    CrossrefPubMedGoogle Scholar
  • 12 Fissore F, Fortunati N, Comba A, Fazzari A, Gaidano G, Berta L, Frairia R. The receptor-mediated action of sex steroid binding protein (SBP, SHBG):accumulation of cAMP in MCF-7 cells under SBP and estradiol treatment.  Steroids. 1994;  59 661-667
    CrossrefPubMedGoogle Scholar
  • 13 Fortunati N. Sex hormone-binding globulin: not only a transport protein. What news is around the corner?.  J Endocrinol Invest. 1999;  22 223-234
    PubMedGoogle Scholar
  • 14 Fortunati N, Fissore F, Fazzari A, Becchis M, Comba A, Catalano MG, Berta L, Frairia R. Sex steroid binding protein exerts a negative control on estradiol action in MCF-7 cells (human breast cancer) through cyclic adenosine 3′,5′-monophosphate and protein kinase A.  Endocrinology. 1996;  137 686-692
    CrossrefPubMedGoogle Scholar
  • 15 Catalano MG, Frairia R, Boccuzzi G, Fortunati N. Sex hormone-binding globulin antagonizes the anti-apoptotic effect of estradiol in breast cancer cells.  Mol Cell Endocrinol. 2005;  230 31-37
    CrossrefPubMedGoogle Scholar
  • 16 Chomzinsky P, Sacchi N. Single-step method of RNA isolation by acid guanidimun thiocyanate-phenol-chloroform extraction.  Anal Biochem. 1987;  162 156-159
    PubMedGoogle Scholar
  • 17 Fazzari A, Catalano MG, Comba A, Becchis M, Raineri M, Frairia R, Fortunati N. The control of progesterone receptor expression in MCF-7 breast cancer cells: effects of estradiol and sex hormone-binding globulin (SHBG).  Mol Cell Endocrinol. 2001;  172 31-36
    CrossrefPubMedGoogle Scholar
  • 18 Thompson CB. Apoptosis in the pathogenesis and treatment of disease.  Science. 1995;  267 1456-1462
    CrossrefPubMedGoogle Scholar
  • 19 Craig RW. The bcl-2 gene family.  Semin Cancer Biol. 1995;  6 35-43
    CrossrefPubMedGoogle Scholar
  • 20 Nahta R, Esteva FJ. Bcl-2 antisense oligonucleotides: a potential novel strategy for the treatment of breast cancer.  Semin Oncol. 2003;  30 143-149
    CrossrefPubMedGoogle Scholar
  • 21 Kandouz M, Siromachkova M, Jacob D, Chretien Marquet B, Therwath A, Gompel A. Antagonism between estradiol and progestin on Bcl-2 expression in breast-cancer cells.  Int J Cancer. 1996;  68 120-125
    CrossrefPubMedGoogle Scholar
  • 22 Lapointe J, Fournier A, Richard V, Labrie C. Androgens down-regulate bcl-2 protooncogene expression in ZR-75-1 human breast cancer cells.  Endocrinology. 1999;  140 416-421
    CrossrefPubMedGoogle Scholar
  • 23 Perillo B, Sasso A, Abbondanza C, Palumbo G. 17β-estradiol inhibits apoptosis in MCF-7 cells, inducing bcl-2 expression via two estrogen-responsive elements present in the coding sequence.  Mol Cell Biol. 2000;  20 2890-2901
    CrossrefPubMedGoogle Scholar
  • 24 Burow ME, Weldon CB, Tang Y, McLachaln JA, Beckman BS. Oestrogen-mediated suppression of tumour necrosis factor alpha-induced apoptosis in MCF-7 cells: subversion of bcl-2 by anti-oestrogens.  J Steroid Biochemistry Molec Biol. 2001;  78 409-418
    PubMedGoogle Scholar
  • 25 Shang Y, Brown M. Molecular determinants for the tissue specificity of SERMs.  Science. 2002;  295 2465-2468
    CrossrefPubMedGoogle Scholar
  • 26 Santoni-Rugiu E, Falck J, Miland N, Bartek J, Lukas J. Involvement of Myc activity in a G(1)/S-promoting mechanism parallel to the pRb/E2F pathway.  Mol Cell Biol. 2000;  20 3497-3509
    CrossrefPubMedGoogle Scholar
  • 27 Hermeking H, Rago C, Schumacher M, Li Q, Barrett JF, Obaya AJ, O'Connell BC, Mateyak MK, Tam W, Kohlhuber F, Dang CV, Sedivy JM, Eick D, Vogelstein B, Kinzler KW. Identification of CDK4 as a target of c-MYC.  Proc Natl Acad Sci USA. 2000;  97 2229-2234
    CrossrefPubMedGoogle Scholar
  • 28 Thiantanawat A, Long BJ, Brodie AM. Signaling pathways of apoptosis activated by aromatase inhbitors and antiestrogens.  Cancer Res. 2003;  63 8037-8050
    PubMedGoogle Scholar
  • 29 Roskoski Jr R. The ErbB/HER receptor protein-tyrosine kinases and cancer.  Biochem. Biophys Res Commun. 2004;  319 1-11
    CrossrefPubMedGoogle Scholar
  • 30 Berthois Y, Dong XF, Martin PM. Regulation of epidermal growth factor-receptor by estrogen and antiestrogen in the human breast cancer cell line MCF-7.  Biochem Biophys Res Commun. 1989;  159 126-131
    CrossrefPubMedGoogle Scholar
  • 31 Ro J, North SM, Gallick GE, Hortobagyi GN, Gutterman JU, Blick M. Amplified and over-expressed epidermal growth factor receptor gene in uncultured primary human breast carcinoma.  Cancer Res. 1988;  48 161-164
    PubMedGoogle Scholar
  • 32 Spyratos F, Delarue JC, Andrieu C, Lidereau R, Champeme MH, Hacene K, Brunet M. Epidermal growth factor receptors and prognosis in primary breast cancer.  Breast Cancer Res Treat. 1990;  17 83-89
    CrossrefPubMedGoogle Scholar
  • 33 Al-Kuraya K, Schraml P, Torhorst J, Tapia C, Zaharieva B, Novotny H, Spichtin H, Maurer R, Mirlacher M, Kochli O, Zuber M, Dieterich H, Mross F, Wilber K, Simon R, Sauter G. Prognostic relevance of gene amplifications and coamplifications in breast cancer.  Cancer Res. 2004;  64 8534-8540
    CrossrefPubMedGoogle Scholar
  • 34 Levin ER. Bidirectional signalling between the estrogen receptor and the epidermal growth factor receptor.  Mol Endocrinol. 2003;  17 309-317
    CrossrefPubMedGoogle Scholar
  • 35 Cidlowski JA, Muldoon TG. The dynamics of intracellular estrogen receptor regulation as influenced by 17beta-estradiol.  Biol Reprod. 1978;  18 234-246
    CrossrefPubMedGoogle Scholar
  • 36 Martin LA, Farmer I, Johnston SR, Ali S, Marshall C, Dowsett M. Enhanced estrogen receptor (ER) alpha, ERBB2, and MAPK signal transduction pathways operate during the adaptation of MCF-7 cells to long term estrogen deprivation.  J Biol Chem. 2003;  278 30458-30468
    CrossrefPubMedGoogle Scholar
  • 37 Truchet I, Jozan S, Guerrin M, Mazzolini L, Vidal S, Valette A. Interconnections between E2-dependent regulation of cell cycle progression and apoptosis in MCF-7 tumors growing on nude mice.  Exp Cell Res. 2000;  254 241-248
    CrossrefPubMedGoogle Scholar
  • 38 Detre S, Salter J, Barnes DM, Riddler S, Hills M, Johnston SR, Gillett C, A'Hern R, Dowsett M. Time-related effects of estrogen withdrawal on proliferation- and cell death-related events in MCF-7 xenografts.  Int J Cancer. 1999;  81 309-313
    CrossrefPubMedGoogle Scholar
  • 39 Fortunati N, Fissore F, Fazzari A, Piovano F, Catalano MG, Becchis M, Berta L, Frairia R. Estradiol induction of cAMP in breast cancer cells is mediated by foetal calf serum (FCS) and sex hormone-binding globulin (SHBG).  J Steroid Biochem Mol Biol. 1999;  70 73-80
    CrossrefPubMedGoogle Scholar
  • 40 Raineri M, Catalano MG, Hammond GL, Avvakumov GV, Frairia R, Fortunati N. O-Glycosylation of human sex hormone-binding globulin is essential for inhibition of estardiol-induced MCF-7 breast cancer cell proliferation.  Mol Cell Endocrinol. 2002;  189 135-143
    CrossrefPubMedGoogle Scholar
  • 41 Coleman KM, Smith CL. Intracellular signaling pathways: nongenomic actions of estrogens and ligand-independent activation of estrogen receptors.  Front Biosci. 2001;  6 1379-1391
    PubMedGoogle Scholar

Correspondence

N. FortunatiM.D. 

Laboratorio Endocrinologia Oncologica

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Italy

Phone: +39/011/6705 360

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Email: nfortunati@molinette.piemonte.it