A potential role for catecholamines in the development and progression of carcinogen-induced mammary tumors: hormonal control of beta-adrenergic receptors and correlation with tumor growth

Abstract

In order to gain further knowledge on the beta-adrenergic receptor system in DMBA-induced rat mammary tumors, we have studied the correlation between changes in tumoral beta-adrenergic receptor concentration and distribution, progesterone receptor status and tumor growth after ovariectomy and treatment with various ovarian and adrenal steroids, or induction of hyperprolactinemia. Autoradiographic localization of beta-adrenergic receptors in ovariectomized (OVX) animals shows very weak labeling with [125I]cyanopindolol. In these tumors, the connective tissue is predominant, while the epithelial cell content is very low. Similarly, when direct measurements of [125I]cyanopindolol are performed with membrane preparations, beta-adrenergic receptor concentration is sharply reduced 2-3 weeks following ovariectomy or treatment with LHRH against [D-Trp6, des-Gly-NH2(10)]LHRH ethylamide. This effect on the beta-adrenergic receptor population in the tumor is accompanied by the well known effect of castration on tumor growth and progesterone receptor levels, namely a marked regression of tumor growth and a significant decrease in progesterone receptor concentration. Treatment of OVX rats with 17 beta-estradiol (E2) alone or in combination with progesterone (P) caused a highly significant increase in beta-adrenergic and progesterone receptor levels, as well as tumor growth. A similar sharp increase in the value of the three parameters studied was observed following daily treatment of OVX rats with dehydroepiandrosterone (DHEA) or androst-5-ene-3 beta,17 beta-diol (5-ene-diol). The autoradiographic localization of beta-adrenergic receptors in OVX rats treated with 5-ene-diol showed that the epithelial cells were numerous with a high degree of labeling. On the other hand, treatment of OVX animals with the androgen dihydrotestosterone (DHT) did not produce significant changes in beta-adrenergic receptor levels or tumor growth. Finally, endogenously-induced hyperprolactinemia by implanting three anterior pituitary glands under the kidney capsule of OVX animals resulted in a significant increase in beta-adrenergic and progesterone receptor levels as well as tumor growth. The positive correlation observed between changes in beta-adrenergic receptor concentration, progesterone receptor levels and tumor growth indicates a high sensitivity of the beta-adrenergic receptor population of DMBA-induced rat mammary tumors to the hormonal milieu, and suggests that the beta-adrenergic receptor system may represent a valuable parameter of hormone responsiveness.