Beta-adrenergic and arachidonic acid-mediated growth regulation of human breast cancer cell lines

Int J Oncol. 2002 Jul;21(1):153-7.

Abstract

Adenocarcinoma of the mammary gland is the leading type of cancer in women. Among these breast cancers those that are estrogen-responsive respond well to existing therapeutic regimens while estrogen non-responsive cancers metastasize widely, demonstrate a high relapse rate, and respond poorly to therapy. Over-expression of the arachidonic acid-metabolizing enzymes cyclooxygenase-2 and lypoxygenases is frequently observed in breast cancer, particularly the non-estrogen-responsive type, suggesting a role of the arachidonic acid (AA) cascade in the growth regulation of these malignancies. Adenocarcinomas of the lungs, pancreas and colon also frequently over-express AA-metabolizing enzymes, and recent evidence suggests that the growth-regulating AA-cascade in these malignancies is under beta-adrenergic control. Our current experiments have therefore tested the hypothesis that in analogy to these findings adenocarcinomas of the breast are also regulated by beta-adrenergic receptors via stimulation of the AA-cascade. Analysis of DNA synthesis by [3H]-thymidine incorporation assays in three estrogen-responsive and three estrogen non-responsive cell lines derived from human breast cancers demonstrated a significant reduction in DNA synthesis by beta-blockers and inhibitors of cyclooxygenase or lipoxygenases in all cell lines. Analysis of AA-release in one of the most responsive cell lines demonstrated a time-dependent increase in AA-release in response to the beta-adrenergic agonist isoproterenol. Analysis by RT-PCR revealed expression of beta2-adrenergic receptors in all cell lines whereas beta1-adrenergic receptors were not found in two of the estrogen non-responsive cell lines. Our data suggest that a significant subset of human breast cancers is under control of beta-adrenergic receptors via stimulation of the AA-cascade. These findings open up novel avenues for the prevention and clinical management of breast cancer, particularly the non-estrogen-responsive types. Moreover, our findings suggest that cardiovascular disease and adenocarcinomas in a variety of organ systems, including the breast may share common risk factors and benefit from similar preventive and treatment strategies.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology*
  • Arachidonate 5-Lipoxygenase / metabolism
  • Arachidonic Acid / metabolism*
  • Aspirin / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cyclooxygenase 2
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors / pharmacology*
  • DNA / biosynthesis
  • DNA Replication / drug effects
  • Enzyme Inhibitors / pharmacology
  • Estrogens / pharmacology
  • Female
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoproterenol / pharmacology
  • Lipoxygenase Inhibitors / pharmacology*
  • Membrane Proteins
  • Neoplasms, Hormone-Dependent / drug therapy
  • Neoplasms, Hormone-Dependent / metabolism
  • Prostaglandin-Endoperoxide Synthases
  • RNA, Messenger / metabolism
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism

Substances

  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Cyclooxygenase 2 Inhibitors
  • Cyclooxygenase Inhibitors
  • Enzyme Inhibitors
  • Estrogens
  • Isoenzymes
  • Lipoxygenase Inhibitors
  • Membrane Proteins
  • RNA, Messenger
  • Receptors, Adrenergic, beta-2
  • Arachidonic Acid
  • DNA
  • Arachidonate 5-Lipoxygenase
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Isoproterenol
  • Aspirin