In order to gain further knowledge about the potential role of
catecholamines in mammary
carcinoma, we have used the potent
beta-adrenergic antagonist cyanopindolol (CYP) as iodinated
ligand to characterize
beta-adrenergic receptors in membranes prepared from mammary
tumors induced by dimethylbenz(a)
anthracene (DMBA) administration in the rat. The binding of [125I]CYP to membrane preparations of DMBA-induced rat mammary
tumors is rapid at room temperature, reaching half maximal specific binding at 30 min of incubation. Scatchard analysis of the data indicates that [125I]CYP binds to a single class of high affinity sites (114 +/- 2.1 fmoles/mg
protein) at an apparent KD value of 38.0 +/- 0.3 pM. The order of potency of a series of agonists to compete for [125I]CYP binding is consistent with interaction with a beta 2-subtype receptor:
zinterol greater than (-)
isoproterenol greater than (-)
epinephrine much greater than (-)
norepinephrine. In addition, the potency of a series of specific beta 1 and beta 2 synthetic compounds to displace [125I]CYP in mammary
tumors is similar to their potency in typical beta 2-adrenergic tissues. The binding of [125I]CYP to DMBA-induced rat mammary
tumors shows a marked stereoselectivity, the (-)isomers of
isoproterenol and
propranolol being 150 and 80 times more potent, respectively, than their respective enantiomers. The autoradiographic localization of [125I]CYP performed on frozen sections revealed the presence of specific
beta-adrenergic receptors in all the malignant cells. Spontaneous mammary
tumors of aging (18-22 months) female rats have high levels of
beta-adrenergic receptors.
Castration decreased the concentration of [125I]CYP binding sites in DMBA-induced mammary
tumors. A close correlation was observed between progressing, static, and regressing
tumors after
ovariectomy and
beta-adrenergic receptor concentration. The presence of
beta-adrenergic receptors in mammary
tumors as well as the modulation of their level by ovarian
hormones provides a mechanism for catecholaminergic influence in
mammary cancer tissue.