Beta-adrenergic receptors in DMBA-induced rat mammary tumors: Correlation with progesterone receptor and tumor growth

Summary In order to gain further knowledge about the potential role of catecholamines in mammary carcinoma, we have used the potent -adrenergic antagonist cyanopindolol (CYP) as iodinated ligand to characterize -adrenergic receptors in membranes prepared from mammary tumors induced by dimethylbenz(a)anthraene (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 K_D 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 ₂-subtype receptor: zinterol > (–)isoproterenol > (–)epinephrine» (–)norepinephrine. In addition, the potency of a series of specific ₁, and ₂ synthetic compounds to displace [¹²⁵I]CYP in mammary tumors is similar to their potency in typical 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 -adrenergic receptors in all the malignant cells. Spontaneous mammary tumors of aging (18–22 months) female rats have high levels of -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 -adrenergic receptor concentration. The presence of -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.