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

• Published in: British journal of pharmacology Vol. 166; no. 2; pp. 721 - 736
• Main Authors: Pérez Piñero, C, Bruzzone, A, Sarappa, MG, Castillo, LF, Lüthy, IA
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-05-2012; Nature Publishing Group
• Subjects: Adrenergic Agonists - pharmacology; Adrenergic Agonists - therapeutic use; Adrenergic Antagonists - pharmacology; Adrenergic Antagonists - therapeutic use; adrenoceptors; Albuterol - pharmacology; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Female; Gynecology. Andrology. Obstetrics; Humans; isoprenaline; Isoproterenol - pharmacology; Mammary gland diseases; mammary tumour; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Pharmacology. Drug treatments; propranolol; Propranolol - pharmacology; rauwolscine; Receptors, Adrenergic, alpha-2 - metabolism; Receptors, Adrenergic, beta-2 - metabolism; Research Papers; salbutamol; Tumors; Xenograft Model Antitumor Assays; Yohimbine - pharmacology; Cell proliferation; Agonist; Isoprenaline; Breast disease; Growth; Pharmacotherapy; β-Adrenergic receptor agonist; β2-Adrenergic receptor; β-Adrenergic receptor; Salbutamol; Antagonist; Mammary gland; Propranolol; mammary tumour; Tumor cell; Drug; α2-Adrenergic receptor; rauwolscine; Bronchodilator; Breast cancer; Malignant tumor; Antiarrhythmic agent; Mammary gland diseases; Treatment; adrenoceptors; Adrenergic receptor; Beta blocking agent; Cancer
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2011.01791.x

BACKGROUND AND PURPOSE β‐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 [3H]‐thymidine incorporation, tumour growth by measuring with a calliper and ERK 1/2 phosphorylation by Western blotting.
KEY RESULTS β2‐Adrenoceptor expression was confirmed in the mouse and human cells tested. Cell proliferation was increased by adrenaline (by α2‐adrenoceptor action) and decreased in every tested cell line by the β‐adrenoceptor agonist isoprenaline and the β2‐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 α2‐adrenoceptor antagonist rauwolscine and the β2‐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 α2‐adrenoceptor antagonist rauwolscine, providing possible novel adjuvant treatments for breast cancer.