Involvement of α2- and β2-adrenoceptors on breast cancer cell proliferation and tumour growth regulation.

background and purposeβ-Adrenoceptors are expressed in human and experimental animal breast cancer cells. However, the effect of the agonists and antagonists reported on cell proliferation and tumour growth was paradoxical, precluding their utilization as possible adjuvant therapy, mainly in the cases of refractory tumours. EXPERIMENTAL APPROACH: β-Adrenoceptor expression was analysed by immunofluorescence and RT-PCR. Cell proliferation was assessed by [(3) H]-thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting. KEY

resultsβ(2) -Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α(2) -adrenoceptor action) and decreased in every tested cell line by the β-adrenoceptor agonist isoprenaline and the β(2) -adrenoceptor agonist salbutamol. Isoprenaline and salbutamol reduced tumour growth in every tumour tested (mouse C4-HD and CC4-3-HI and human IBH-4, IBH-6 and MDA-MB-231 cell lines growing as xenografts in nude mice). These effects were reversed by the β-adrenoceptor antagonist propranolol. The α(2) -adrenoceptor antagonist rauwolscine and the β(2) -adrenoceptor agonist salbutamol were equally effective in diminishing tumour growth. ERK 1/2 activation analysed in IBH-4 tumours correlated with tumour growth, with the β-adrenoceptor agonists decreasing its activation. Inhibition of ERK 1/2 phosphorylation in vitro was mainly mediated by the PKA pathway. CONCLUSIONS AND IMPLICATIONS: In our experimental models, the β-adrenoceptor agonists inhibited breast cancer cell proliferation and tumour growth, probably mediated by inhibition of ERK 1/2 phosphorylation. The β-adrenoceptor agonists were as effective as the α(2) -adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer.