Beta-adrenergic inhibition of cell proliferation and tumor growth in breast cancer models.

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Breast cancer, the most common cancer amid women in the majority of the countries, is also among the most feared of diseases. The principal effectors of the stress system include the catecholamines epinephrine and norepinephrine, which bind to α₁-, α₂- and β-adrenoceptors (AR). Our group has recently described α₂-AR in human breast cell lines, associated with enhanced cell proliferation. The expression of β₂-AR has been described in different experimental models for breast cancer.
 The aim of the present work was to assess the action of β-adrenergic agonists and antagonists on cell proliferation and tumor growth.
 We have confirmed the expression of β-AR in the human HS-578T cell line and in the murine MC4-L5 one by immunofluorescence using specific antibodies against β₂-AR and α₂-AR (1:100 final dilution).
 Cell proliferation was then analyzed using [³H]-thymidine incorporation in the presence of the natural adrenergic agonist (epinephrine, EPI) and a specific β-adrenergic specific agonist (isoproterenol, ISO). Cell proliferation was significantly enhanced after the treatment with EPI in the murine MC4-L5 cells, EC50=0.13 pM, in the human HS-578T cell line, EC50=0.16 nM. ISO induced a significant decline in [³H]-thymidine incorporation in both cell lines with values of EC50=1.4 pM and 17nM for MC4-L5 and HS-578T respectively.
 The in vivo effect of a β-adrenergic agonist and antagonist was then assessed in the mouse mammary progestin-independent tumor CC4-3-HI transplanted to 2 months-old Balb/c mice and human breast cancer MDA-MB-231 cells growing in nude mice. The administration of 1mg/kg of the β-adrenergic agonist ISO to Balb/c mice significantly diminished tumor growth. As an example, on day 24: 1148.4 ± 212.1 mm³ vs. 2556.7 ± 187.4, p<0.01; 1 mg/Kg of the β-antagonist propanolol (PRO) reversed this effect (2150,1 ± 216 mm³), without any effect of the antagonist alone (1744.3 ± 194 mm³). When the human breast cancer MDA-MB-231 inoculated to nude mice (7x10^-6 cells sc) were analyzed, a similar result was found. For example, on day 50: ISO: 63.37 ± 35.3 mm³ vs. 360.7 ± 108.3 mm³ p<0.05; ISO + PRO, (361.2 ± 155.9 mm³) without any per se effect (208.0 ± 72.2 mm³). 
 We conclude that epinephrine is acting mainly through α₂-ARs, which are associated with enhanced cell proliferation and that the β-adrenergic agonist inhibits both cell proliferation and tumor growth. These compounds, devoid of serious side-effects, could eventlually be employed to inhibit tumor growth.