Insights into cardio-oncology: adrenergic receptor signaling and pathways in breast cancer.

Insights into cardio-oncology: adrenergic receptor signaling and pathways in breast cancer. Re: Du Y, Zhou L, Wang Y, et al. Association of alpha2a and beta2 adrenoceptor expression with clinical outcome in breast cancer. Curr Med Res Opin 2014: published online 21 March 2014

Dear Editor,

I have read with great interest the excellent article by Du et al.1. Nowadays cardiotoxicity prevention still remains an important challenge along with its surveillance and management in cancer survivors2–5. Research has emphasized both cardioprotective beta adrenergic receptor blocker (BB) use against cardiotoxic chemiotherapies2–5 and the activation of the sympathetic nervous system as a target for regulation of breast cancer, and it has also suggested a possible role for targeted breast cancer therapy using BBs6^,7. Although research has confirmed continuous use of BBs as being associated with cardioprotective lower incidence of heart failure5^,8 and with reducing related psychological distress9 in patients with breast cancer, there is retrospective evidence suggesting that the use of BBs in early stage breast cancer patients correlates with an increased time to recurrence2^,10. The Commonly used Medications and Breast Cancer Outcomes (COMBO) cohort has indicated BB use warrants further evaluation with respect to second primary breast cancer11 and greater attention has been focused regarding breast cancer outcomes12. Recently, although most individual BBs have shown no association with recurrence of breast cancer, metoprolol and sotalol have been associated with increased recurrence rates of breast cancer12 and a little evidence of an association between post-diagnostic BB usage and breast cancer progression has also been reported2^,13. In view of these opposing data, research was performed on PubMed regarding a possible explanation. Research has suggested a breast cell proliferation increase by the α2-adrenergic receptor agonist adrenaline14. Notably a highly selective α2-adrenergic receptor agonist dexmedetomidine increases tumor growth and metastasis15^,16. The α2-adrenergic receptor agonist clonidine increases tumor growth17. The α2-adrenergic receptor antagonist rauwolscine diminishes tumor growth14^,17. The HERG ligand16 α1-adrenergic receptor antagonist doxazosin18 suppressed haptotactic and chemotactic migration of breast cancer cells and is capable of inhibiting malignant behaviors in vitro and in vivo18–21. A breast cell proliferation decrease and a breast cancer growth reduction by the β-adrenergic receptor agonist isoprenaline and by the β2-adrenergic receptor agonist salbutamol14 have been reported probably due to extracellular-signal-regulated kinases ERK1/2 phosphorylation inhibition. These effects are reversed by the β-adrenergic receptor blocker (BB) propranolol14. Moreover, expression of mRNA encoding a G-protein coupled inwardly rectifying potassium channel (GIRK1) has shown in human breast cancers20^,21 to be associated with more aggressive clinical behavior and its increase appears after almost 6 days of continuous exposure to BB propranolol21. In addition salbutamol exerts androgen-dependent inhibition of proliferation of the androgen receptor (AR)-positive human mammary carcinoma22. Moreover research confirms beta-adrenergic receptor agonists decrease breast cancer cell lines viability23 and that β-adrenergic receptor agonist isoprenaline decreases breast cancer cell migration24. The excellent article published1 confirms the findings regarding the association of β2 adrenoceptor expression with clinical outcome in breast cancer and it is welcome. There is a need for large studies to clear apparently conflicting observations and to improve our understanding of the relevance of the role of adrenergic receptor signaling and pathways in breast cancer but the way is open. All efforts to expand the evidence base in cardio-oncology8^,25 may help to promote new strategies for patients’ safety and to encourage patients in their heavy cancer journey.

Sincerely,

Salvatore Patanè MD

Cardiologia Ospedale San Vincenzo – Taormina (Me) Azienda Sanitaria Provinciale di Messina, Italy Contrada Sirina, 98039 Taormina (Messina), Italy Tel.: [phone]; [email protected]

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Declaration of funding

This letter was not funded.

Declaration of financial/other relationships

S.P. has disclosed that he has no significant relationships with or financial interests in any commercial companies related to this study or article.