Molecular Oncology
Volume 4, Issue 2 , Pages 135-149 , April 2010

Testosterone membrane-initiated action in breast cancer cells: Interaction with the androgen signaling pathway and EPOR

  • Vassiliki Pelekanou

      Affiliations

    • Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece
    • Present address: Laboratoire d'Anatomie Pathologique, Institut Jules Bordet-Centre des Tumeurs de l'ULB, Rue Héger-Bordet 1, 1000 Brussels, Belgium.
    • Authors have equal contribution.
  • ,
  • George Notas

      Affiliations

    • Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece
    • Authors have equal contribution.
  • ,
  • Elias Sanidas

      Affiliations

    • Department of Surgical Oncology, University of Crete, School of Medicine, Heraklion GR-71003, Greece
  • ,
  • Andreas Tsapis

      Affiliations

    • INSERM, U976, Paris, F-75010 France
    • INSERM, Univ Paris-Diderot, Paris, F-75013 France
  • ,
  • Elias Castanas

      Affiliations

    • Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece
    • Corresponding Author InformationCorresponding authors. Tel.: +30 2810 394580; fax: +30 2810 394581.
  • ,
  • Marilena Kampa

      Affiliations

    • Laboratory of Experimental Endocrinology, University of Crete, School of Medicine, P.O. Box 2208, Heraklion GR-71003, Greece
    • Corresponding Author InformationCorresponding authors. Tel.: +30 2810 394580; fax: +30 2810 394581.

Received 16 December 2009 ,Revised 21 January 2010 ,Accepted 22 January 2010.

References 

  1. Acconcia F, Ascenzi P, Bocedi A, Spisni E, Tomasi V, Trentalance A, et al. Palmitoylation-dependent estrogen receptor alpha membrane localization: regulation by 17beta-estradiol. Mol. Biol. Cell. 2005;16:231–237
  2. Acconcia F, Ascenzi P, Fabozzi G, Visca P, Marino M. S-palmitoylation modulates human estrogen receptor-alpha functions. Biochem. Biophys. Res. Commun. 2004;316:878–883
  3. Acs G, Chen M, Xu X, Acs P, Verma A, Koch CJ. Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells. Cancer Lett. 2004;214:243–251
  4. Agoff SN, Swanson PE, Linden H, Hawes SE, Lawton TJ. Androgen receptor expression in estrogen receptor-negative breast cancer. Immunohistochemical, clinical, and prognostic associations. Am. J. Clin. Pathol. 2003;120:725–731
  5. Agrawal AK, Jelen M, Grzebieniak Z, Zukrowski P, Rudnicki J, Nienartowicz E. Androgen receptors as a prognostic and predictive factor in breast cancer. Folia Histochem. Cytobiol. 2008;46:269–276
  6. Alexaki VI, Charalampopoulos I, Kampa M, Nifli AP, Hatzoglou A, Gravanis A, et al. Activation of membrane estrogen receptors induce pro-survival kinases. J. Steroid. Biochem. Mol. Biol. 2006;98:97–110
  7. Alexaki VI, Charalampopoulos I, Panayotopoulou M, Kampa M, Gravanis A, Castanas E. Dehydroepiandrosterone protects human keratinocytes against apoptosis through membrane binding sites. Exp. Cell. Res. 2009;315:2275–2283
  8. Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002;359:2131–2139
  9. Benten WP, Guo Z, Krucken J, Wunderlich F. Rapid effects of androgens in macrophages. Steroids. 2004;69:585–590
  10. Benten WP, Lieberherr M, Stamm O, Wrehlke C, Guo Z, Wunderlich F. Testosterone signaling through internalizable surface receptors in androgen receptor-free macrophages. Mol. Biol. Cell. 1999;10:3113–3123
  11. Bonaccorsi L, Muratori M, Carloni V, Marchiani S, Formigli L, Forti G, et al. The androgen receptor associates with the epidermal growth factor receptor in androgen-sensitive prostate cancer cells. Steroids. 2004;69:549–552
  12. Brys M, Wojcik M, Romanowicz-Makowska H, Krajewska WM. Androgen receptor status in female breast cancer: RT-PCR and Western blot studies. J. Cancer Res. Clin. Oncol. 2002;128:85–90
  13. Chen L, Mayer JA, Krisko TI, Speers CW, Wang T, Hilsenbeck SG, et al. Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells. Cancer Res. 2009;
  14. Cheng J, Watkins SC, Walker WH. Testosterone activates mitogen-activated protein kinase via Src kinase and the epidermal growth factor receptor in sertoli cells. Endocrinology. 2007;148:2066–2074
  15. Dambaki C, Kogia C, Kampa M, Darivianaki K, Nomikos M, Anezinis P, et al. Membrane testosterone binding sites in prostate carcinoma as a potential new marker and therapeutic target: study in paraffin tissue sections. BMC Cancer. 2005;5:148
  16. De Amicis, F., Thirugnansampanthan, J., Cui, Y., Selever, J., Beyer, A., Parra, I., Weigel, N.L., Herynk, M.H., Tsimelzon, A., Lewis, M.T., et al., Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res. Treat. in press.
  17. Dimitrakakis C, Bondy C. Androgens and the breast. Breast Cancer Res. 2009;11:212
  18. Falkenstein E, Norman AW, Wehling M. Mannheim classification of nongenomically initiated (rapid) steroid action(s). J. Clin. Endocrinol. Metab. 2000;85:2072–2075
  19. Farrell F, Lee A. The erythropoietin receptor and its expression in tumor cells and other tissues. Oncologist. 2004;9(Suppl. 5):18–30
  20. Hall SA, Araujo AB, Kupelian V, Maserejian NN, Travison TG. Testosterone and breast cancer. J. Sex. Med. 2009;
  21. Hardee ME, Cao Y, Fu P, Jiang X, Zhao Y, Rabbani ZN, et al. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE. 2007;2:e549
  22. Hatzoglou A, Kampa M, Kogia C, Charalampopoulos I, Theodoropoulos PA, Anezinis P, et al Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J. Clin. Endocrinol. Metab. 2005;90:893–903
  23. Heinlein CA, Chang C. The roles of androgen receptors and androgen-binding proteins in nongenomic androgen actions. Mol. Endocrinol. 2002;16:2181–2187
  24. Jelkmann W, Bohlius J, Hallek M, Sytkowski AJ. The erythropoietin receptor in normal and cancer tissues. Crit. Rev. Oncol. Hematol. 2008;67(1):39–61
  25. Kaarbo M, Klokk TI, Saatcioglu F. Androgen signaling and its interactions with other signaling pathways in prostate cancer. Bioessays. 2007;29:1227–1238
  26. Kampa M, Castanas E. Membrane steroid receptor signaling in normal and neoplastic cells. Mol. Cell. Endocrinol. 2006;246:76–82
  27. Kampa M, Kogia C, Theodoropoulos PA, Anezinis P, Charalampopoulos I, Papakonstanti EA, et al Activation of membrane androgen receptors potentiates the antiproliferative effects of paclitaxel on human prostate cancer cells. Mol. Cancer Ther. 2006;5:1342–1351
  28. Kampa M, Nifli AP, Charalampopoulos I, Alexaki VI, Theodoropoulos PA, Stathopoulos EN, et al. Opposing effects of estradiol- and testosterone-membrane binding sites on T47D breast cancer cell apoptosis. Exp. Cell Res. 2005;307:41–51
  29. Kampa M, Papakonstanti EA, Alexaki VI, Hatzoglou A, Stournaras C, Castanas E. The opioid agonist ethylketocyclazocine reverts the rapid, non-genomic effects of membrane testosterone receptors in the human prostate LNCaP cell line. Exp. Cell Res. 2004;294:434–445
  30. Kampa M, Papakonstanti EA, Hatzoglou A, Stathopoulos EN, Stournaras C, Castanas E. The human prostate cancer cell line LNCaP bears functional membrane testosterone receptors that increase PSA secretion and modify actin cytoskeleton. FASEB J. 2002;16:1429–1431
  31. Kampa M, Pelekanou V, Castanas E. Membrane-initiated steroid action in breast and prostate cancer. Steroids. 2008;73:953–960
  32. Karin M, Yang-Yen HF, Chambard JC, Deng T, Saatcioglu F. Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. Eur. J. Clin. Pharmacol. 1993;45(Suppl. 1):S9–S15discussion S43–4
  33. Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N. Engl. J. Med. 2007;356:2445–2448
  34. Lacombe C, Mayeux P. The molecular biology of erythropoietin. Nephrol. Dial Transpl. 1999;14(Suppl. 2):22–28
  35. Lai SY, Childs EE, Xi S, Coppelli FM, Gooding WE, Wells A, et al. Erythropoietin-mediated activation of JAK-STAT signaling contributes to cellular invasion in head and neck squamous cell carcinoma. Oncogene. 2005;24:4442–4449
  36. Liebermann DA, Hoffman B. Gadd45 in stress signaling. J. Mol. Signal. 2008;3:15
  37. Lim LY, Vidnovic N, Ellisen LW, Leong CO. Mutant p53 mediates survival of breast cancer cells. Br. J. Cancer. 2009;101:1606–1612
  38. Liu YN, Liu Y, Lee HJ, Hsu YH, Chen JH. Activated androgen receptor downregulates E-cadherin gene expression and promotes tumor metastasis. Mol. Cell. Biol. 2008;28:7096–7108
  39. Loesch M, Chen G. The p38 MAPK stress pathway as a tumor suppressor or more?. Front Biosci. 2008;13:3581–3593
  40. Miki Y, Suzuki T, Sasanoa H. Intracrinology of sex steroids in ductal carcinoma in situ (DCIS) of human breast: comparison to invasive ductal carcinoma (IDC) and non-neoplastic breast. J. Steroid Biochem. Mol. Biol. 2009;114:68–71
  41. Nicolas Diaz-Chico B, German Rodriguez F, Gonzalez A, Ramirez R, Bilbao C, Cabrera de Leon A, et al. Androgens and androgen receptors in breast cancer. J. Steroid Biochem. Mol. Biol. 2007;105:1–15
  42. Niemeier LA, Dabbs DJ, Beriwal S, Striebel JM, Bhargava R. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation. Mod. Pathol. 2009;
  43. Nifli AP, Bosson-Kouame A, Papadopoulou N, Kogia C, Kampa M, Castagnino C, et al. Monomeric and oligomeric flavanols are agonists of membrane androgen receptors. Exp. Cell Res. 2005;309:329–339
  44. Noguchi CT, Bae KS, Chin K, Wada Y, Schechter AN, Hankins WD. Cloning of the human erythropoietin receptor gene. Blood. 1991;78:2548–2556
  45. Notas, G., Pelekanou, V., Castanas, E., Kampa, M. Conjugated and non-conjugated androgens differentially modulate specific early gene transcription in breast cancer in a cell-specific manner. Steroids, in press. doi:10.1016/j.steroids.2009.1010.1004.
  46. Papakonstanti EA, Kampa M, Castanas E, Stournaras C. A rapid, nongenomic, signaling pathway regulates the actin reorganization induced by activation of membrane testosterone receptors. Mol. Endocrinol. 2003;17:870–881
  47. Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, et al. Expression of androgen receptors in primary breast cancer. Ann. Oncol. 2009;
  48. Pedram A, Razandi M, Kim JK, O'Mahony F, Lee EY, Luderer U, et al. Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse. J. Biol. Chem. 2009;284:3488–3495
  49. Pedram A, Razandi M, Levin ER. Nature of functional estrogen receptors at the plasma membrane. Mol. Endocrinol. 2006;20:1996–2009
  50. Pelekanou V, Kampa M, Kafousi M, Dambaki K, Darivianaki K, Vrekoussis T, et al. Erythropoietin and its receptor in breast cancer: correlation with steroid receptors and outcome. Cancer Epidemiol. Biomark. Prev. 2007;16:2016–2023
  51. Peters AA, Buchanan G, Ricciardelli C, Bianco-Miotto T, Centenera MM, Harris JM, et al Androgen receptor inhibits estrogen receptor-alpha activity and is prognostic in breast cancer. Cancer Res. 2009;69:6131–6140
  52. Recchione C, Venturelli E, Manzari A, Cavalleri A, Martinetti A, Secreto G. Testosterone, dihydrotestosterone and oestradiol levels in postmenopausal breast cancer tissues. J. Steroid Biochem. Mol. Biol. 1995;52:541–546
  53. Secreto G, Recchione C, Ballerini P, Callegari L, Cavalleri A, Attili A, et al. Accumulation of active androgens in breast cyst fluids. Eur. J. Cancer. 1991;27:44–47
  54. Secreto G, Venturelli E, Bucci A, Piromalli D, Fariselli G, Galante E. Intratumour amount of sex steroids in elderly breast cancer patients. An approach to the biological characterization of mammary tumours in the elderly. J. Steroid Biochem. Mol. Biol. 1996;58:557–561
  55. Secreto G, Venturelli E, Meneghini E, Greco M, Ferraris C, Gion M, et al Testosterone and biological characteristics of breast cancers in postmenopausal women. Cancer Epidemiol. Biomark. Prev. 2009;18:2942–2948
  56. Shibuya R, Suzuki T, Miki Y, Yoshida K, Moriya T, Ono K, et al Intratumoral concentration of sex steroids and expression of sex steroid-producing enzymes in ductal carcinoma in situ of human breast. Endocr. Relat. Cancer. 2008;15:113–124
  57. Shufelt CL, Braunstein GD. Testosterone and the breast. Menopause Int. 2008;14:117–122
  58. Shufelt CL, Braunstein GD. Safety of testosterone use in women. Maturitas. 2009;63:63–66
  59. Sieri S, Krogh V, Bolelli G, Abagnato CA, Grioni S, Pala V, et al Sex hormone levels, breast cancer risk, and cancer receptor status in postmenopausal women: the ORDET cohort. Cancer Epidemiol. Biomark. Prev. 2009;18:169–176
  60. Solomon SS, Majumdar G, Martinez-Hernandez A, Raghow R. A critical role of Sp1 transcription factor in regulating gene expression in response to insulin and other hormones. Life Sci. 2008;83:305–312
  61. Spinola PG, Marchetti B, Merand Y, Belanger A, Labrie F. Effects of the aromatase inhibitor 4-hydroxyandrostenedione and the antiandrogen flutamide on growth and steroid levels in DMBA-induced rat mammary tumors. Breast Cancer Res. Treat. 1988;12:287–296
  62. Spivak JL. The anaemia of cancer: death by a thousand cuts. Nat. Rev. Cancer. 2005;5:543–555
  63. Stellacci E, Di Noia A, Di Baldassarre A, Migliaccio G, Battistini A, Migliaccio AR. Interaction between the glucocorticoid and erythropoietin receptors in human erythroid cells. Exp. Hematol. 2009;37:559–572
  64. Suzuki T, Miki Y, Akahira J, Moriya T, Ohuchi N, Sasano H. Aromatase in human breast carcinoma as a key regulator of intratumoral sex steroid concentrations. Endocr. J. 2008;55:455–463
  65. Suzuki T, Miki Y, Moriya T, Akahira J, Hirakawa H, Ohuchi N, et al. In situ production of sex steroids in human breast carcinoma. Med. Mol. Morphol. 2007;40:121–127
  66. Suzuki T, Miki Y, Ohuchi N, Sasano H. Intratumoral estrogen production in breast carcinoma: significance of aromatase. Breast Cancer. 2008;15:270–277
  67. Szego CM, Davis JS. Adenosine 3′,5′-monophosphate in rat uterus: acute elevation by estrogen. Proc. Natl. Acad. Sci. U S A. 1967;58:1711–1718
  68. Thornton TM, Rincon M. Non-classical p38 map kinase functions: cell cycle checkpoints and survival. Int. J. Biol. Sci. 2009;5:44–51
  69. Wehling M. Specific non-genomic effects of steroid hormones. Annu. Rev. Physiol. 1997;59:365–393
  70. Weidemann A, Johnson RS. Biology of HIF-1alpha. Cell Death Differ. 2008;15:621–627
  71. Yasuda Y, Fujita Y, Matsuo T, Koinuma S, Hara S, Tazaki A, et al Erythropoietin regulates tumour growth of human malignancies. Carcinogenesis. 2003;24:1021–1029
  72. Yin F, Bruemmer D, Blaschke F, Hsueh WA, Law RE, Herle AJ. Signaling pathways involved in induction of GADD45 gene expression and apoptosis by troglitazone in human MCF-7 breast carcinoma cells. Oncogene. 2004;23:4614–4623
  73. Zarubin T, Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15:11–18

PII: S1574-7891(10)00005-0

doi: 10.1016/j.molonc.2010.01.004

Molecular Oncology
Volume 4, Issue 2 , Pages 135-149 , April 2010