Beta-adrenergic receptors in DMBA-induced rat mammary tumors: correlation with progesterone receptor and tumor growth.
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.
Marchetti
B
B
MRC Group in Molecular Endocrinology, Laval University Medical Center, Quebec, Canada.
Spinola
P G
PG
Plante
M
M
Poyet
P
P
Folléa
N
N
Pelletier
G
G
Labrie
F
F
D015127:9,10-Dimethyl-1,2-benzanthracene; D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D002395:Catecholamines / Q000378:metabolism; D005260:Female; D006728:Hormones / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism / Q000648:ultrastructure*; D009365:Neoplasm Regression, Spontaneous; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D010052:Ovariectomy; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000378:metabolism; D013379:Substrate Specificity
D000319:Adrenergic beta-Antagonists; D002395:Catecholamines; D006728:Hormones; D007457:Iodine Radioisotopes; D011943:Receptors, Adrenergic, beta; D011980:Receptors, Progesterone; C047975:cyanopindolol; D015127:9,10-Dimethyl-1,2-benzanthracene; D010869:Pindolol