Skip to main content
SpringerLink
Log in

β-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells

  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

MDA-MB-231 human breast cancer cells express high β-adrenoceptor levels, predominantly the β2 subtype. Receptor stimulation by isoproterenol evoked immediate reductions in DNA synthesis which were blocked completely by propranolol and were of the same magnitude as effects elicited by high concentrations of 8-Br-cAMP. Isoproterenol-induced inhibition of DNA synthesis was maintained throughout several days of exposure, resulting in a decrement in total cell number, and the effects were augmented by cotreatment with dexamethason; an even greater effect was seen when cAMP breakdown was inhibited by theophylline, with or without addition of isoproterenol. Despite the persistent effect of isoproterenol, receptor downregulation was evident with as little as 1 h of treatment, and over 90% of the receptors were lost within 24 h. Receptor downregulation was paralleled by homologous desensitization of the adenylyl cyclase response to β-adrenoceptor stimulation. Dexamethasone augmented the effects of isoproterenol on DNA synthesis but did not prevent receptor downregulation or desensitization. These results indicate that β-adrenoceptors are effectively linked, through cAMP, to the termination of cell replication in MDA-MB-231 human breast cancer cells, and that activation of only a small number of receptors is sufficient for a maximal effect. Novel pharmacologic strategies that focus on cell surface receptors operating through adenylyl cyclase may offer opportunities to combat cancers that are unresponsive to hormonal agents, or that have developed multidrug resistance.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Buznikov GA, Kost AN, Berdysheva LV: The role of neurohumours in early embryogenesis. 3. Pharmacological analysis of the role of neurohumours in cleavage divisions. J Embryol Exp Morphol 23: 549–569, 1970

    Google Scholar 

  2. Vernadakis A, Gibson DA: Role of neurotransmitter substances in neural growth. In: Dancis J, Hwang JC (eds) Perinatal Pharmacology: Problems and Priorities. Raven Press, New York, 1974, pp 65–76

    Google Scholar 

  3. Lovell J: Effects of 6-hydroxydopamine-induced norepinephrine depletion on cerebellar development. Dev Neurosci 5: 359–368, 1982

    Google Scholar 

  4. Slotkin TA, Whitmore WL, Orband-Miller L, Queen KL, Haim K: Beta adrenergic control of macromolecule synthesis in neonatal rat heart, kidney and lung: relationship to sympathetic neuronal development. J Pharmacol Exp Ther 243: 101–109, 1987

    Google Scholar 

  5. Claycomb WC: Biochemical aspects of cardiac muscle differentiation. J Biol Chem 251: 6082–6089, 1976

    Google Scholar 

  6. Slotkin TA, Levant B, Orband-Miller L, Queen KL, Stasheff S: Do sympathetic neurons coordinate cellular development in the heart and kidney? Effects of neonatal central and peripheral catecholaminergic lesions on cardiac and renal nucleic acids and proteins. J Pharmacol Exp Ther 244: 166–172, 1988

    Google Scholar 

  7. Rohrer DK, Desai KH, Jasper JR, Stevens ME, Regula DP, Barsh GS, Bernstein D, Kobilka BK: Targeted disruption of the mouse β1-adrenergic receptor gene: developmental and cardiovascular effects. Proc Natl Acad Sci 93: 7375–7380, 1996

    Google Scholar 

  8. Thomas SA, Matsumoto AM, Palmiter RD: Noradrenaline is essential for mouse fetal development. Nature 374: 643–646, 1995

    Google Scholar 

  9. Zhou QY, Quaife CJ, Palmiter RD: Targeted disruption of the tyrosine hydroxylase gene reveals that catecholamines are required for mouse fetal development. Nature 374: 640–643, 1995

    Google Scholar 

  10. Wagner JP, Seidler FJ, Schachat FH, Slotkin TA: Beta adrenergic control of c-fos protooncogene expression in developing rat brain regions. J Pharmacol Exp Ther 269: 1292–1299, 1994

    Google Scholar 

  11. Zeng T, Yamamoto H, Bowen E, Broverman RL, Nguyen KHT, Humphreys-Beher MG: Cell cycle control in isoproterenol-induced murine salivary acinar cell proliferation. Comp Biochem Physiol 115: 271–279, 1996

    Google Scholar 

  12. Ling L, Haraguchi K, Ohta K, Endo T, Onaya T: β2-Adrenergic receptor mRNA is overexpressed in neoplastic human thyroid tissues. Endocrinology 130: 547–549, 1992

    Google Scholar 

  13. Re G, Badino P, Novelli A, Girardi C, DiCarlo F: Evidence for functional β-adrenoceptor subtypes in CG-5 breast cancer cells. Pharmacol Res 33: 255–260, 1996

    Google Scholar 

  14. MacEwan DJ, Milligan G: Up-regulation of a constitutively active form of the β2-adrenoceptor by sustained treatment with inverse agonists but not antagonists. FEBS Lett 399: 108–112, 1996

    Google Scholar 

  15. Canova C, Baudet C, Chevalier G, Brachet P, Wion D: Noradrenaline inhibits the programmed cell death induced by 1,25-dihydroxyvitamin D-3 in glioma. Eur J Pharmacol 319: 365–368, 1997

    Google Scholar 

  16. Mitra SP, Carraway RE: Synergistic effects of neurotensin and β-adrenergic agonist on 3′,5′-cyclic adenosine monophosphate accumulation and DNA synthesis in prostate cancer PC3 cells. Biochem Pharmacol 57: 1391–1397, 1999

    Google Scholar 

  17. Re G, Badino P, Girardi C, Di Carlo F: Effects of a β2-agonist, clenbuterol, on cultured human (CG-5) breast cancer cells. Pharmacol Res 26: 377–384, 1992

    Google Scholar 

  18. Yand J, Guzman R, Richards J, Imagawa W, McCormick K, Nandi S: Growth factor and cyclic nucleotide-induced proliferation of normal and malignant mammary epithelial cells. Endocrinology 107: 35–41, 1980

    Google Scholar 

  19. Chen J, Bander JA, Santore TA, Chen Y, Ram PT, Smit MJ, Iyengar R: Expression of Q227L-Gαs in MCF-7 human breast cancer cells inhibits tumorigenesis. Proc Natl Acad Sci 95: 2648–2652, 1998

    Google Scholar 

  20. Slotkin TA, Windh R, Whitmore WL, Seidler FJ: Adrenergic control of DNA synthesis in developing rat brain regions: effects of intracisternal administration of isoproterenol. Brain Res Bull 21: 737–740, 1988

    Google Scholar 

  21. Duncan CP, Seidler FJ, Lappi SE, Slotkin TA: Dual control of DNA synthesis by α-and β-adrenergic mechanisms in normoxic and hypoxic neonatal rat brain. Dev Brain Res 55: 29–33, 1990

    Google Scholar 

  22. Stiles GL: Mechanisms of receptor activation in adenylate cyclase. J Cardiovasc Pharmacol 14: S1–S5, 1989

    Google Scholar 

  23. Giannuzzi CE, Seidler FT, Slotkin TA: β-Adrenoceptor control of cardiac adenylyl cyclase during development: agonist pretreatment in the neonate uniquely causes heterologous sensitization, not desensitization. Brain Res 694: 271–278, 1995

    Google Scholar 

  24. Zeiders JL, Seidler FJ, Slotkin TA: Ontogeny of regulatory mechanisms for β-adrenoceptor control of rat cardiac adenylyl cyclase: targeting of G-proteins and the cyclase catalytic subunit. J Mol Cell Cardiol 29: 603–615, 1997

    Google Scholar 

  25. Zeiders JL, Seidler FJ, laccarino G, Koch WJ, Slotkin TA: Ontogeny of cardiac β-adrenoceptor desensitization mechanisms: agonist treatment enhances receptor/G-protein transduction rather than eliciting uncoupling. J Mol Cell Cardiol 31: 413–423, 1999

    Google Scholar 

  26. Vandewalle B, Revillion F, Lefebvre J: Functional β-adrenergic receptors in breast cancer cells. J Cancer Res Clin Oncol 116: 303–306, 1990

    Google Scholar 

  27. Slotkin TA, Lau C, McCook EC, Lappi SE, Seidler FJ: Glucocorticoids enhance intracellular signaling via adenylate cyclase at three distinct loci in the fetus: a mechanism for heterologous teratogenic sensitization? Toxicol Appl Pharmacol 127: 64–75, 1994

    Google Scholar 

  28. Bell TM, Whitmore WL, Slotkin TA: Effects of α-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase, on nucleic acids and proteins in developing rat brain: critical perinatal periods for regional selectivity. Neuroscience 17: 399–407, 1986

    Google Scholar 

  29. Chaudhry A, Granneman JG: Developmental changes in adenylyl cyclase and GTP binding proteins in brown fat. Amer J Physiol 261: R403–R411, 1991

    Google Scholar 

  30. Navarro HA, Kudlacz EM, Slotkin TA: Control of adenylate cyclase activity in developing rat heart and liver: effects of prenatal exposure to terbutaline or dexamethasone. Biol Neonate 60: 127–136, 1991

    Google Scholar 

  31. Snedecor GW, Cochran WG: Statistical Methods. Iowa State University Press, Ames, Iowa, 1967

    Google Scholar 

  32. Cailleau R, Young R, Olive M, Reeves WJ: Breast tumor cell lines from pleural effusions. J Natl Cancer Inst 53: 661–674, 1974

    Google Scholar 

  33. Slotkin TA, Lau C, Seidler FJ: β-Adrenergic receptor overexpression in the fetal rat: distribution, receptor subtypes and coupling to adenylate cyclase via G-proteins. Toxicol Appl Pharmacol 129: 223–234, 1994

    Google Scholar 

  34. Marchetti B, Spinola PG, Pelletier G, Labrie F: A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: hormonal control of β-adrenergic receptors and correlation with tumor growth. J Steroid Biochem Mol Biol 38: 307–320, 1991

    Google Scholar 

  35. Draoui A, Vandewalle B, Hornez L, Revillion F, Lefebvre J: β-Adrenergic receptors in human breast cancer: identification, characterization and correlation with progesterone and estradiol receptors. Anticancer Res 11: 677–680, 1991

    Google Scholar 

  36. Thai L, Galluzzo JM, McCook EC, Seidler FJ, Slotkin TA: Atypical regulation of hepatic adenylyl cyclase and adrenergic receptors during a critical developmental period: agonists evoke supersensitivity accompanied by failure of receptor downregulation. Pediatr Res 39: 697–707, 1996

    Google Scholar 

  37. Amadori D, Silvestrini R: Prognostic and predictive value of thymidine labelling index in breast cancer. Breast Cancer Res Treat 51: 267–281, 1998

    Google Scholar 

  38. Homburger V, Lucas M, Rosenbaum E, Vassent G, Bockaert J: Presence of both β1-and β2-adrenergic receptors in a single cell type. Mol Pharmacol 20: 463–469, 1981

    Google Scholar 

  39. Wagner JP, Seidler FJ, Lappi SE, McCook EC, Slotkin TA: Role of presynaptic input in the ontogeny of adrenergic cell signaling in rat brain: beta receptors, adenylate cyclase, and c-fos protooncogene expression. J Pharmacol Exp Ther 273: 415–426, 1995

    Google Scholar 

  40. Davies AO, Lefkowitz RJ: Regulation of β-adrenergic receptors by steroid hormones. Ann Rev Physiol 46: 119–130, 1984

    Google Scholar 

  41. Shmukier YB, Buznikov GA: Functional coupling of neurotransmitters with second messengers during cleavage divisions: facts and hypotheses. Perspect Dev Neurobiol 5: 469–483, 1998

    Google Scholar 

  42. Fennell M, Khawaja XZ, Cockett MI, Wood A: Enhanced neuronal differentiation of NTera-2 cells expressing neuronally restricted β2 adrenergic receptor. Brain Res 799: 243–249, 1998

    Google Scholar 

  43. Mirossay L, Chastre E, Empereur S, Gespach C: Cyclic AMPresponsive gene transcription in cellular proliferation and transformation (review). Int J Oncol 1: 373–385, 1992

    Google Scholar 

  44. Moens U, Subramaniam N, Johansen B, Aarbakke J: The c-fos cAMP-response element: regulation of gene expression by a β2-adrenergic agonist, serum and DNA methylation. Biochim Biophys Acta 1173: 63–70, 1993

    Google Scholar 

  45. Barnes CD, Eltherington LG: Drug Dosage in Laboratory Animals: A Handbook. Revised edition. Univ. of California Press, Berkeley, CA, 1973

    Google Scholar 

  46. Bian X, Seidler FJ, Olsen C, Raymond JR, Slotkin TA: Effects of fetal dexamethasone exposure on postnatal control of cardiac adenylate cyclase: β-adrenergic receptor coupling to Gs regulatory protein. Teratology 48: 169–177, 1993

    Google Scholar 

  47. Cros GH, Chanez PO, Michel A, Boucard M, Serrano J-J: Post-natal evolution of rat cardiac beta-adrenoceptors. Life Sci 43: 699–706, 1988

    Google Scholar 

  48. Zagon IS, Hytrek SD, Lang CM, Smith JP, McGarrity TJ, Wu Y, McLaughlin PJ: Opioid growth factor ([Met5]enkephalin) prevents the incidence and retards the growth of human colon cancer. Amer J Physiol 271: R780–R786, 1996

    Google Scholar 

  49. Hytrek SD, McLaughlin PJ, Lang CM, Zagon IS: Inhibition of human colon cancer by intermittent opioid receptor blockade with naltrexone. Cancer Lett 101: 159–164, 1996

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

    Theodore A. Slotkin, Jian Zhang, Ria Dancel, Stephanie J. Garcia, Carrie Willis & Frederic J. Seidler

Authors
  1. Theodore A. Slotkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ria Dancel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stephanie J. Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carrie Willis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Frederic J. Seidler
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Slotkin, T.A., Zhang, J., Dancel, R. et al. β-adrenoceptor signaling and its control of cell replication in MDA-MB-231 human breast cancer cells. Breast Cancer Res Treat 60, 153–166 (2000). https://doi.org/10.1023/A:1006338232150

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1006338232150

Search

Navigation