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.