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. 2012 May;4(3):113–125. doi: 10.1177/1758834012439738

Beta-adrenergic blocking drugs in breast cancer: a perspective review

Thomas I Barron 1,✉, Linda Sharp 2, Kala Visvanathan 3
PMCID: PMC3349076  PMID: 22590485

Abstract

The purpose of this review is to present the preclinical, epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression. Preclinical studies have shown that β-adrenergic receptor (β-AR) signalling can inhibit multiple cellular processes involved in breast cancer progression and metastasis, including extracellular matrix invasion, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses. This has led to the hypothesis that the commonly prescribed class of β-AR antagonist drugs (β-blockers) may favourably impact cancer progression. A number of recent pharmacoepidemiological studies have examined the association between β-blocker exposure and breast cancer progression. The results from these studies have suggested a potential role for targeting the β-AR pathway in breast cancer patients. Larger observational studies are, however, required to confirm these results. Questions regarding the type of β-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy must also be answered in randomized clinical studies before β-blockers can be considered a therapeutic option for patients with breast cancer.

Keywords: adrenergic beta-agonists, adrenergic beta-antagonists, adrenergic receptors, breast neoplasms, neoplasms, propranolol

Introduction

The importance of host factors in cancer aetiology and outcome has been highlighted recently [Goodwin et al. 2010]. Epidemiological and clinical studies have associated psychosocial factors such as chronic stress and depression with cancer progression and, to a lesser extent, cancer onset [Spiegel et al. 2007; Chida et al. 2008]. These effects are mediated in part through activation of the autonomic nervous system and the hypothalamic–pituitary–adrenal axis, causing the release of catecholamines, glucocorticoids and other stress hormones from the adrenal gland, brain and sympathetic nerve terminals [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Lutgendorf et al. 2010]. In this review we focus on the sympathetic nervous system component of the physiological stress response, which results in release of epinephrine and norepinephrine. Both of these neurotransmitters have been shown in preclinical studies to impact several pathways necessary for tumour progression and metastasis through direct tumour effects and indirect effects on the tumour microenvironment [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Goodwin et al. 2010; Lutgendorf et al. 2010]. Specifically, these studies have demonstrated that the protumour and prometastatic effects of epinephrine and norepinephrine are mediated primarily through the β-adrenergic receptor (β-AR) signalling pathway. This has led a number of authors to hypothesize that the commonly prescribed class of β-AR antagonist drugs (β-blockers) may favourably impact cancer progression [Entschladen et al. 2004; Antoni et al. 2006; Thaker et al. 2007; Armaiz-Pena et al. 2009; Lutgendorf et al. 2010]. The purpose of this review is to present the epidemiological and clinical data relevant to the association between β-blockers and breast cancer progression within the context of current preclinical evidence [Pérez-Sayáns et al. 2010]. The effects of β-blockers on breast cancer incidence will not be discussed.

Preclinical studies

β-Adrenergic receptor expression in breast cancer

β-Adrenergic receptors are Gs-protein-coupled receptors that activate adenylate cyclase to elevate intracellular 3′,5′-cyclic adenosine monophosphate (cAMP) and activate protein kinase A. There are three β-AR subtypes, β1-AR, β2-AR and β3-AR, each with specific physiological actions. The expression of β-ARs has been characterized in several breast cancer cell lines [Vandewalle et al. 1990; Badino et al. 1996; Slotkin et al. 2000; Sloan et al. 2010; Madden et al. 2011; Park et al. 2011; Shi et al. 2011] as well as in collections of human breast cancer tissue samples [Draoui et al. 1991; Powe et al. 2011; Shi et al. 2011] and in mammary tumours from rodents induced by administration of dimethylbenz(a)anthracene [Marchetti et al. 1991] (see Table 1). Studies have shown that these β-ARs are predominantly of the β2-adrenergic receptor (β2-AR) subtype [Draoui et al. 1991; Badino et al. 1996; Slotkin et al. 2000] and are functionally active, with pharmacological ligation resulting in significant cAMP production [Vandewalle et al. 1990; Badino et al. 1996; Slotkin et al. 2000; Sloan et al. 2010; Madden et al. 2011].

Table 1.

Overview of studies examining β-adrenergic receptor expression in breast cancer cell lines and tumour samples.

Study Breast cell type ER+ PR+ HER-2+ β-AR β1-AR β2-AR Comments/functional significance
Marchetti et al. [1991] Induced rodent mammary tumours – – – Yes – – Influence of oestrogen levels on β-AR concentration assessed. Ovariectomy reduced β-AR expression and subsequent treatment with oestrogen caused a significant increase in β-AR levels.
Vandewalle et al. [1990] MCF-7 Yes Yes No Low – – β-AR agonists stimulated cAMP production in a dose-dependent manner. Response was greatest in the triple-negative MDA-MB-231 cell line. The pathophysiological significance of this was not studied.
T47-D Yes – – Low – –
MDA-MB-231 No No No High – –
BT-20 No No No Low – –
VHB-1 Yes – – Low – –
Badino et al. [1996] CG-5 Yes – – Yes Yes Yes The ratio of β2-AR to β1-AR expression was 3:1. β-AR agonists stimulated cAMP production in a dose-dependent manner. The pathophysiological significance of this was not studied.
Slotkin et al. [2000] MDA-MB-231 No No No High No High β-AR agonists reduced DNA synthesis and cell replication.
Sloan et al. [2010] 66cl4 No No No Low – Low β-AR agonists stimulated cAMP production. The pathophysiological significance of this was unclear as the effects of β-AR signalling on the development of tumour metastases were shown to be mediated through induction of tumour macrophage infiltration.
Madden et al. [2011] MCF-7 Yes Yes No Low – Low β-AR agonists stimulated cAMP production in proportion to β-AR expression levels. β-AR stimulation induced VEGF expression in the MDA-MB-231BR cell line but not others.
MDA-MB-361 Yes – Yes Low – Low
MDA-MB-231 No No No High – High
MDA-MB-231BR No No No High – High
Shi et al. [2011] MCF-7 Yes Yes No Low – Low β-AR expression was strongly correlated with HER-2 expression in cell lines and clinical samples. β-AR expression was upregulated in MCF-7(HER-2) cells overexpressing HER-2. Suggestion that β2-AR and HER-2 expression comprises a positive feedback loop in human breast cancer cells.
BT-474 No Yes Yes High – Low
MDA-MB-435 No No Yes High – High
MCF-7(HER-2) Yes Yes Yes High – High
Human breast tumour samples – – – Yes – Yes
Draoui et al. [1991] Human breast tumour samples – – – Yes No Yes β-AR normally coupled with G-protein. A slight correlation was shown between β-AR and PR, and no correlation between β-AR and ER.
Powe et al. [2011] Human breast tumour samples – – – Yes – Yes β-AR expression was negative in 2%, weak in 42% and strong in 55% of samples. β-AR expression was significantly associated with tumours of small size, low histological grade, early clinical stage, and ER and PR expression. High expression was associated with a nonsignificant increase in survival.
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ER, oestrogen receptor; PR, progesterone receptor; HER-2, human epidermal growth factor receptor 2; β-AR, β-adrenergic receptor; β1-AR, β1-adrenergic receptor; β2-AR, β2-adrenergic receptor, VEGF, vascular endothelial growth factor; cAMP, cyclic adenosine monophosphate.

Although β2-AR is expressed by both oestrogen receptor (ER)-positive and ER-negative breast cancer cell lines, the highest levels of expression have been observed in cell lines that are ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor receptor 2 (HER-2)-negative (triple-negative breast cancer [TNBC]) [Vandewalle et al. 1990; Madden et al. 2011]. This has led to suggestions that the β2-AR signalling may be of greatest significance in the pathogenesis and progression of TNBC [Melhem-Bertrandt et al. 2011]. Results from studies in human breast cancer tissue samples have not been as consistent as those of studies in cell lines [Draoui et al. 1991; Powe et al. 2011; Shi et al. 2011]. In a study by Draoui and colleagues, the authors reported only a weak correlation between β-AR and PR expression and no correlation with the ER [Draoui et al. 1991]. However, in a recent study of breast tumour samples from 690 women [Powe et al. 2011], β2-AR expression was strongly correlated with ER and PR expression, 80% and 65% of tumours with high β2-AR expression co-expressing ER and PR respectively. There was no correlation between β2-AR and HER-2 expression in this study, although a correlation has been noted in another study of both clinical samples and breast cancer cell lines [Shi et al. 2011]. β-Blocker use by patients included in these breast tumour sample studies was not reported.

The prognostic significance of β2-AR expression is also unclear. In the study by Powe and colleagues, patients with high levels of β2-AR expression had a nonsignificant increase in survival when compared with patients with low-level expression [Powe et al. 2011]. The authors suggest that this may be due to the observed association between β2-AR expression and small ER-positive tumours of low clinical stage and low proliferation. In unadjusted Kaplan–Meier analyses they also observed among ER-positive tumours a decrease in survival for tumours that co-expressed β2-AR, which may reflect interactions between the ER and β2-AR. However, further analyses are necessary before drawing such conclusions. A recently published abstract has also suggested that β-AR expression was not correlated with an observed association between β-blocker exposure and improved outcomes in women with breast cancer [Powe et al. 2010a]. It is, however, possible that the effects of β-AR signalling in breast cancer may be independent of β-AR expression by breast tumour cells. β2-AR signalling may impact breast cancer progression through its effects on tumour immune responses and the regulation of the tumour microenvironment.

Blocking β-adrenergic receptor signalling in breast cancer

Preclinical studies have shown that antagonism of β-AR signalling by a β-blocker can inhibit multiple cellular processes involved in breast cancer progression, including tumour cell proliferation, metastasis development, apoptosis, extracellular matrix invasion, matrix metalloprotease activation, expression of inflammatory and chemotactic cytokines, angiogenesis and tumour immune responses (see Table 2).

Table 2.

Overview of preclinical studies examining the effects of β-adrenergic receptor signalling in breast cancer.

Study Breast cell type Model Tumour characteristic β-AR agonist effect β-AR antagonist effect (β-blockers)
Re et al. [1992] CG-5 In vitro Tumour growth β-AR signalling (pharmacological agonists) stimulated tumour growth. –
Slotkin et al. [2000] MDA-MB-231 In vitro Tumour growth β2-AR signalling (pharmacological agonists) inhibited tumour growth through a cAMP activated pathway. Inhibited by the β1/β2-AR nonselective antagonist propranolol. Propranolol itself had no effect on tumour growth.
Drell et al. [2003] MDA-MB-468 In vitro Migration and invasion β-AR signalling (pharmacological agonists) stimulated tumour cell migration. Promigratory effects of β-AR signalling were completely inhibited by the β2-AR-selective antagonist ICI-118.551 and partially inhibited by the β1-AR-selective antagonist atenolol.
Lang et al. [2004] MDA-MB-468 In vitro Migration and invasion β2-AR signalling (pharmacological agonists) stimulated tumour cell migration. Promigratory effects of β2-AR signalling were inhibited by the β1/β2-AR-nonselective antagonist propranolol.
Melamed et al. [2005] MADB106 In vivo Metastasis β-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis. Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist nadolol. Effect of nadolol was greater in combination with the COX1/COX2 inhibitor indomethacin.
Immune response
Thaker et al. [2006] MDA-MB-231 In vivo Tumour growth β2-AR signalling (pharmacological agonists and stress-induced) stimulated tumour growth, tumour angiogenesis and metastatic spread. –
Angiogenesis
Metastasis
Carie and Sebti [2007] MDA-MB-231 In vitro Tumour growth β2-AR signalling (pharmacological agonists) inhibited tumour growth in vitro and induced in vivo tumour regression through cAMP activation, and subsequent inhibition of the RAF-1/MEK-1/ERK-1,2 pathway. Inhibited by β2-AR-selective antagonist ICI-118.551.
In vivo Cell death
Benish et al. [2008] MADB106 In vivo Metastasis β-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis. Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist propranolol. Effect of propranolol was greater in combination with the COX2 inhibitor etodolac.
Immune response
Avraham et al. [2010] MADB106 In vivo Metastasis β-AR signalling (surgical stress induced) inhibited natural killer cell cytotoxicity against tumour cells and increased metastasis. Reduced natural killer cell activity and increased metastasis inhibited by the β1/β2-AR-nonselective antagonist nadolol in combination with the COX1/COX2 inhibitor indomethacin and immune stimulant poly I-C.
Immune response
Sloan et al. [2010] 66cl4 In vivo Metastasis β2-AR signalling (pharmacological agonists and stress-induced) induced 30-fold increase in metastasis to distant tissues. Effects mediated by tumour macrophage infiltration and production of the pro-angiogenic and prometastatic factors VEGF and MMP-9. Tumour metastasis, macrophage infiltration and angiogenesis were Inhibited by the β1/β2-AR-nonselective antagonist propranolol. Propranolol had no effect on primary tumour growth.
Angiogenesis
Immune response
Shi et al. [2011] MCF-7 In vitro Tumour growth β2-AR signalling (pharmacological agonists) stimulated the expression of HER-2 and induced tumour growth in a dose-dependent manner. β-AR signalling also upregulated production of the pro-angiogenic and prometastatic factors VEGF and IL-8. Expression of HER-2 was inhibited by the β2-AR-selective antagonist ICI-118.551.
Angiogenesis
Metastasis
Madden et al. [2011] MCF-7 In vitro Angiogenesis β2-AR signalling (pharmacological agonists) stimulated production of pro-angiogenic factors VEGF (MDA-MB-231BR) and IL-6 (MDA-MB-231BR and MDA--MB-231) Production of the pro-angiogenic factors VEGF and IL-6 inhibited by the β2-AR-selective antagonist ICI-118.551.
MDA-MB-361
MDA-MB-231
MDA-MB-231BR
Park et al. [2011] MDA-MB-231 Angiogenesis β2-AR signalling (pharmacological agonists) stimulated production of the pro-angiogenic factor VEGF via a HIF-1α-dependent pathway. Upregulation of VEGF and HIF-1α expression were inhibited by the β1/β2-AR-nonselective antagonist propranolol.
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β-AR, β-adrenergic receptor; β2-AR, β2-adrenergic receptor; VEGF, vascular endothelial growth factor; IL, interleukin; COX, cyclooxygenase; HIF, hypoxia-inducible factor ; Poly I-C, Polyinosinic:polycytidylic acid.

Tumour growth

There is evidence to suggest that β-AR signalling plays a role in the regulation of tumour growth in a number of cancers; however, the evidence relating to breast tumour growth is conflicting. β-AR stimulation has been shown to both inhibit [Slotkin et al. 2000; Carie and Sebti, 2007] and promote breast tumour growth [Re et al. 1992; Cakir et al. 2002; Thaker et al. 2006; Shi et al. 2011], and more recent studies report that β-AR signalling has negligible effect on in vitro or in vivo breast tumour growth [Sloan et al. 2010; Madden et al. 2011]. The reasons for such heterogeneity are not entirely clear. Results from ovarian cancer models have demonstrated that the effect of β-AR signalling on tumour growth is associated with β2-AR expression by tumour cells [Thaker et al. 2006]. This does not appear to be the case for breast cancer, for which studies using cell lines with high β2-AR expression have produced opposing results [Slotkin et al. 2000; Thaker et al. 2006; Carie and Sebti, 2007; Madden et al. 2011]. In one of these studies, the effect β-AR stimulation on tumour growth varied across β-AR agonist type. This has led to the suggestion that differences between β-AR agonists may contribute to functional heterogeneity in breast cancer cell responses to β-AR stimulation [Madden et al. 2011]. It is also possible that the direct effects of β-AR signalling on the tumour microenvironment may explain the observed differences between studies conducted in vivo and in vitro [Sloan et al. 2010]. In ovarian cancer models, β-AR stimulation has been consistently shown to promote tumour growth [Thaker et al. 2006; Landen et al. 2007; Lee et al. 2009]. This effect, as noted, is associated with tumour cell β-AR expression, mediated through the β2-AR and inhibited by the β-blocker propranolol (β1/β2-AR nonselective) [Thaker et al. 2006; Landen et al. 2007; Lee et al. 2009]. Similar results have been observed in pancreatic and oesophageal cancer [Liu et al. 2008; Zhang et al. 2009].

Tumour metastasis

Several in vivo breast cancer studies have shown that β-AR signalling is involved in the pathogenesis of breast cancer metastases [Melamed et al. 2005; Benish et al. 2008; Avraham et al. 2010; Sloan et al. 2010]. In these studies either stress-induced or pharmacological β-AR stimulation resulted in up to a 30-fold increase in metastasis to distant sites, including the lymph nodes and lung. β-Blockers (propranolol, nadolol; β1/β2-AR-nonselective) inhibited these prometastatic effects by between 50% and 100%. Greater inhibition was also obtained by combining these β-blockers with prostaglandin synthesis inhibitors (cyclooxygenase [COX] 1 and COX2 inhibitors, e.g. indomethacin) and immune stimulants. [Melamed et al. 2005; Benish et al. 2008; Avraham et al. 2010]. The prometastatic effects of β-AR signalling have also been demonstrated in melanoma and ovarian, lung and prostate cancer [Palm et al. 2006; Thaker et al. 2006; Glasner et al. 2010]. β-AR signalling promotes the development of tumour metastases through the regulation of several key steps in the pathogenesis of metastasis. These include tumour vascularization, invasion, migration, survival in circulation and the evasion of tumour immune responses [Lutgendorf et al. 2010].

Cell death

Preclinical studies have demonstrated conflicting effects of β-AR signalling in the regulation of tumour cell apoptosis and anoikis. Carie and colleagues demonstrated that the β2-AR agonist ARA-211 induced breast tumour cell apoptosis in vitro and tumour regression in vivo [Carie and Sebti, 2007]. However, Sastry and colleagues determined that signalling via the β2-AR reduces the sensitivity of prostate cancer cells to apoptosis [Sastry et al. 2007]. Sood and colleagues also showed that the β-AR agonists epinephrine and norepinephrine protected ovarian tumour cells from anoikis and that this effect was inhibited by the β1/β2-nonselective antagonist propranolol [Sood et al. 2010]. Two further studies have also shown that inhibition of β2-AR signalling by propranolol or a β2-adrenergic receptor- specific antagonist in combination with gemcitabine induces apoptosis in pancreatic cancer cells [Zhang et al. 2009; Shan et al. 2011]. In these studies the β1-AR-selective antagonist metoprolol had the least effect on apoptotic rate [Zhang et al. 2009].

Angiogenesis

β-AR signalling has been shown to increase the in vitro [Madden et al. 2011; Park et al. 2011; Shi et al. 2011] and in vivo [Thaker et al. 2006; Sloan et al. 2010] expression of vascular endothelial growth factor (VEGF) and interleukin (IL)-6, key pro-angiogenic factors, in a number of breast tumour models. This stimulation of VEGF expression by β-AR signalling is proportional to β-AR expression [Madden et al. 2011], dose-dependent [Park et al. 2011] and inhibited by propranolol [Park et al. 2011]. There have, however, been discrepancies between the results from in vitro and in vivo studies of β-AR signalling and VEGF expression [Thaker et al. 2006; Madden et al. 2011]. It has been suggested that these discrepancies may be attributed to in vivo VEGF production by β-AR-expressing cells in the tumour stroma (i.e. macrophages) [Thaker et al. 2006]. This suggestion has subsequently been confirmed [Sloan et al. 2010]. In vivo studies have associated β-AR-induced increases in VEGF production with significant increases in breast tumour vasculature [Thaker et al. 2006; Sloan et al. 2010]. These studies have focused on the role of β2-AR signalling in breast tumour angiogenesis, but have not ruled out the possibility that other members of the β-AR family may also play a role. Studies in other tumour types have, however, shown that the effects of adrenergic signalling are mediated primarily through the β2-AR [Liu et al. 2008; Zhang et al. 2010]. The stimulatory effects of β-AR signalling on VEGF expression have been observed in ovarian [Lutgendorf et al. 2003; Thaker et al. 2006; Lee et al. 2009], nasopharyngeal [Yang et al. 2006], melanoma [Yang et al. 2009], oesophageal [Liu et al. 2008], multiple myeloma [Yang et al. 2008], prostate [Park et al. 2011] and pancreatic [Guo et al. 2009; Zhang et al. 2010] tumour models. Also of interest has been the recent chance discovery that the nonselective β-blocker propranolol is an effective treatment for infantile haemangioma, a common benign tumour occurring in 5–10% of infants [Schiestl et al. 2011]. It has been suggested that the observed benefits of treatment are due in most part to the inhibition of VEGF production by propranolol [Storch and Hoeger, 2010].

Migration and invasion

In vitro breast cancer models have shown that the β-AR agonist norepinephrine exerts both chemokinetic and chemoattractive effects on breast tumour cells [Drell et al. 2003; Lang et al. 2004]. In these studies, norepinephrine exposure positively influenced the number and direction of migrating tumour cells. Similar findings have been reported for several other tumour types, including ovarian, colon, prostate and pancreatic cancers [Masur et al. 2001; Lang et al. 2004; Sood et al. 2006; Zhang et al. 2010]. In vivo studies of these promigratory and pro-invasive effects have also demonstrated an association between norepinephrine exposure, increased invasiveness, nodal involvement and the development of metastasis [Palm et al. 2006; Sood et al. 2006]. It has been shown that these effects are mediated through the β-AR pathway, primarily the β2-AR, and are inhibited by nonselective β-blockers, for example propranolol [Masur et al. 2001; Drell et al. 2003; Lang et al. 2004; Palm et al. 2006; Sood et al. 2006; Zhang et al. 2010]. Similar inhibitory effects have not been uniformly observed with the use of β1-AR-selective antagonists such as atenolol [Masur et al. 2001; Drell et al. 2003; Lang et al. 2004; Zhang et al. 2010]. β-AR signalling regulates the migratory and invasive capacity of tumour cells through alterations in tumour gene expression and the upregulation of matrix metalloproteinase (MMP) expression (MMP-2, MMP-9) [Sood et al. 2006; Landen et al. 2007; Zhang et al. 2010]. Pharmacological blockade of these MMPs has been shown to inhibit the effects of β-AR signalling on tumour cell invasive potential [Sood et al. 2006].

Immune response

β-AR signalling plays an important role in the regulation of tumour-directed immune responses. Two studies have demonstrated, using in vivo breast tumour models, that β-AR agonists suppress natural killer cell activity in a dose-dependent manner, resulting in a 10-fold increase in the number of tumour cells retained in the lungs and a similar rise in the number of consequent lung metastases [Melamed et al. 2005; Benish et al. 2008]. Further confirmation of these results was obtained in studies demonstrating that the perioperative use of propranolol and a COX2 inhibitor regulates the immune response, reduces the risk of postoperative tumour metastasis and improves recurrence-free survival rates in mice undergoing primary tumour excision [Avraham et al. 2010; Glasner et al. 2010]. β-AR signalling also appears to regulate the prometastatic effects of the tumour immune response. Sloan and colleagues used an in vivo model of breast cancer to demonstrate that either stress-induced or pharmacological adrenergic stimulation resulted in a considerable increase in the development of metastases [Sloan et al. 2010]. This effect was mediated through β2-AR signalling, which promoted the infiltration of macrophages into the primary tumour parenchyma and induced a prometastatic gene expression signature. Macrophages were shown to be the intratumoral target of this β2-AR signalling, which resulted in the increased expression of macrophage-derived factors, including COX2, MMP-9 and VEGF, the last of which was associated with a threefold increase in tumour blood vessel density. Treatment with the β-blocker propranolol inhibited macrophage infiltration, tumour spread to distant tissues and the vascularization of tumours.

β-Blockers in breast cancer: pharmacoepidemiological studies

Six recently published pharmacoepidemiological studies have examined the association between β-blocker exposure and breast cancer progression. In the first of these studies, published in October 2010, Powe and colleagues reviewed medical records to identify female patients with stage I and II breast cancer presenting to the Nottingham City Hospital, UK, between 1987 and 1994 [Powe et al. 2010b]. These patients were then classified into one of three subgroups: women with a history of hypertension receiving a β-blocker for at least 1 year prior to diagnosis (n = 43, β1-AR-selective 74%, β1/β2-AR-non-selective 26%); women with a history of hypertension at the time of breast cancer diagnosis receiving other antihypertensive drug treatment for at least 1 year prior to diagnosis (n = 49); and normotensive women (n = 374) not on any antihypertensive drugs. Women receiving β-blocker treatment for less than 1 year were excluded from the study. The time to distant metastasis formation and breast cancer-specific survival was compared between all three groups using multivariate analyses. These demonstrated a 57% reduced risk of metastasis development (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.20–0.93) and a 71% reduction in the risk of breast cancer-specific mortality after 10 years (HR 0.29; 95% CI 0.12–0.72) after adjusting for tumour size, stage and grade in women taking any β-blocker compared with those who were not.

In a subsequent study by Ganz and colleagues the authors examined associations between any β-blocker exposure and/or angiotensin converting enzyme inhibitor (ACEi) exposure and breast cancer outcomes [Ganz et al. 2011]. The Life After Cancer Epidemiology (LACE) cohort was used to identify 1779 women enrolled from the Kaiser Permanente Northern California Cancer Registry with a diagnosis of early-stage invasive breast cancer between 1997 and 2000. β-Blocker and ACEi exposure in the year before and after breast cancer diagnosis was identified for each patient in this cohort from pharmacy dispensing records. They identified 407 women who filled at least one prescription for a β-blocker or an ACEi during this period. This number comprised 66 patients who filled a prescription for both, 137 who filled a prescription for an ACEi only and 204 who filled a prescription for a β-blocker only (β1-AR-selective 82%, β1/β2-AR-nonselective 18%). The time to breast cancer recurrence, breast cancer-specific mortality and overall mortality was compared between exposed and unexposed groups using delayed-entry Cox proportional hazards models adjusted for age, race, tumour stage, hormone receptor status, chemotherapy and hormonal therapy use, body mass index, hypertension and diabetes. In comparison with unexposed women, women taking β-blockers had a nonsignificant 14% reduction in the risk of breast cancer recurrence (HR 0.86; 95% CI 0.57–1.32) and a nonsignificant 24% reduction in the risk of breast cancer-specific mortality (HR 0.76; 95% CI 0.44–1.33). There was, however, no reduction in all-cause mortality (HR 1.04; 95% CI 0.72–1.51). ACEi exposure was unexpectedly associated with a significant increase in breast cancer recurrence and cause-specific mortality.

Four further studies were published in 2011 [Barron et al. 2011; Melhem-Bertrandt et al. 2011; Sendur et al. 2011; Shah et al. 2011]. In the study by Melhem-Bertrandt and colleagues, the authors used the Breast Cancer Management System Database at The University of Texas MD Anderson Cancer Center to identify 102 women with invasive breast cancer, treated with neoadjuvant chemotherapy from January 1995 to May 2007 who also reported taking a β-blocker (β1-AR-selective 89%, β1/β2-AR nonselective 11%) and 1311 patients taking no β-blockers. There was no difference in the rate of pathological complete response between women taking and not taking β-blockers. Relapse-free survival and overall survival were also compared between the two groups. Women taking β-blockers had a 48% reduction in the risk of breast cancer recurrence (HR 0.52; 95% CI 0.31–0.88) and a nonsignificant 36% reduction in the risk of death (HR 0.64; 95% CI 0.38–1.07) after adjusting for age, stage, race, body mass index, comorbidities and medication usage. In further subgroup analyses β-blocker use was associated with a 70% reduction in breast cancer recurrence (HR 0.30; 95% CI 0.10–0.87) among patients with TNBC (n = 377) and a nonsignificant 65% reduction in mortality (HR 0.35; 95% CI 0.12–1.00). β-Blocker use had no significant association with relapse-free survival and overall survival among women with ER-positive (n = 826) breast cancer. The study authors suggest that the relatively short follow-up time in their study (median follow-up 55 months) may have limited the ability to detect an association in this population.

In the study by Barron and colleagues, we used linked national cancer registry and prescription refill data from Ireland to identify 5801 women with a diagnosis of stage I–IV invasive breast cancer between 2001 and 2006 [Barron et al. 2011]. From this population, women taking propranolol only (n = 70, β1/β2-nonselective), atenolol only (n = 525, β1-selective) or no β-blocker (n = 4738) at any time in the year prior to diagnosis were identified. Separate matched (ratio 1:2) analyses were conducted to examine associations between the use of propranolol or atenolol and the risk of local tumour invasion at diagnosis (T4 tumour), nodal or metastatic involvement at diagnosis (N2/N3/M1 tumour) and breast cancer-specific mortality. In comparison with nonusers, propranolol users were less likely to present with a T4 tumour (odds ratio [OR] 0.24; 95% CI 0.07–0.85) or N2/N3/M1 tumour (OR 0.20; 95% CI 0.04–0.88). Women taking propranolol at the time of diagnosis (n = 47) had an 81% lower risk of breast cancer-specific mortality (HR 0.19; 95% CI 0.06–0.60) after adjusting for age, stage, grade and comorbidity score. No association with invasive tumour characteristics (T4 tumour: OR 1.31; 95% CI 0.91–1.88. N2/N3/M1 tumour: OR 1.10; 95% CI 0.72–1.71) or breast cancer-specific mortality (HR 1.08; 95% CI 0.84–1.40) was observed for patients taking the β1-selective antagonist atenolol.

In the study by Shah and colleagues, the authors used the DIN-LINK primary care database in the UK to identify 3462 women with a primary diagnosis of breast (n = 984), colorectal (n = 619), lung (n = 436), oesophagus (n = 159), ovarian (148), pancreas (n = 140), prostate (n = 759), renal (n = 124) or stomach (n = 93) cancer between 1997 and 2006, and at least two prescriptions for an antihypertensive agent in the year prior to diagnosis [Shah et al. 2011]. Patients with coronary heart disease, heart failure, stroke or arrhythmias before cancer diagnosis were excluded, as were patients with a contraindication for β-blocker or other antihypertensive therapy. The 1406 patients taking a β-blocker were compared with 2056 patients taking other antihypertensive therapy. The proportions of all patients taking selective and nonselective β-blockers were 83% and 17%, respectively. Information on selective/nonselective β-blocker use by cancer subtype was not provided. In the breast cancer analysis, there was no difference in overall survival (HR 1.09; 95% CI 0.80–1.49) between patients receiving any β-blocker (n = 434) and patients receiving other antihypertensive medications (n = 554) after adjusting for age, sex, year of diagnosis, smoking status, number of medications received in the year before diagnosis, socioeconomic status and national region. However, data on treatment received and prognostic tumour characteristics, such as stage, grade and receptor status, were not available. In addition, the use of patients receiving antihypertensives other than a β-blocker as a comparator group makes the interpretation of the results from this study difficult. This is because there is evidence to suggest that a number of these antihypertensive drugs may also influence breast cancer outcomes [Ganz et al. 2011].

In the study by Sendur and colleagues, the authors report the results from an age-matched retrospective analysis of breast cancer outcomes in users (n = 88) and nonusers (n = 456) of the β1-AR-selective antagonist metoprolol [Sendur et al. 2011]. There were no significant differences in 3-year disease-free or 5-year overall survival rates between metoprolol users and nonusers. This analysis was, however, not adjusted for relevant prognostic and confounding variables.

Overall, the results from these pharmacoepidemiological studies suggest a potential role for targeting the β-AR pathway in breast cancer patients. There are, however, differences between their results that raise a number of important questions. Firstly, preclinical data indicate that it is β2-AR signalling that plays the most prominent role in breast tumour regulation. Yet in the studies by Powe, Ganz and Melhem-Bertrandt and their colleagues the most commonly used β-blockers were β1-AR-selective antagonists (74–89%) [Powe et al. 2010b; Ganz et al. 2011; Melhem-Bertrandt et al. 2011]. It has been suggested that the observed associations with these agents may be due to the fact that many β1-AR-selective β-blockers have relatively large off-target β2-AR receptor affinity, and that even modest β2-AR antagonism may be sufficient to inhibit the effects of β2-AR signalling [Ganz and Cole, 2011]. However, this assumption is not strongly supported by preclinical studies, which have shown relatively little effect for β1-AR antagonists, or the results from our study [Barron et al. 2011], in which no effect on breast cancer outcomes was observed for atenolol, a β1-AR-selective antagonist with a β1:β2 adrenergic receptor affinity of 6:1 [Smith and Teitler, 1999]. It is difficult to draw definitive conclusions about the possible effects of β1-AR-selective agents from the studies by Powe, Ganz and Melhem Bertrandt and their colleagues, as all of these studies included both β1-selective and β1/β2-nonselective antagonists in the same analyses. Understanding of the relative effects of β1-selective and β1/β2-nonselective antagonists therefore requires further clarification and future pharmacoepidemiological studies should, if possible, report their results stratified by β-AR subtype.

The second question raised by the results from these studies regards the possible variation in the effect of β-blockers with respect to ER, PR and HER-2 status. Results from the study by Melhem-Bertrandt and colleagues suggest that the effects of β-blocker exposure are most evident in patients with TNBC [Melhem-Bertrandt et al. 2011]. A significant benefit from β-blocker exposure was not observed for ER-positive patients in their study. Unfortunately, the studies by Powe, Ganz and Shah and their colleagues and ourselves did not, or were unable to, distinguish between these different breast cancer subtypes and are thus unable to confirm this observation. The rationale for undertaking a subgroup analysis in TNBC patients was based upon the observation that TNBC patients have a higher prevalence of abdominal obesity and metabolic syndrome, both of which are linked to dysregulation of the sympathetic nervous system and potentially increased β-AR signalling [Melhem-Bertrandt et al. 2011]. Further work is required to clarify whether the clinical effects of β-blockers vary according to β-AR expression or ER, PR and HER-2 status.

In addition to these remaining questions, future pharmacoepidemiological studies should address questions regarding associations between breast cancer outcomes and β-blocker dose or duration. Also of interest will be the timing of β-blocker exposure with respect to other anti-cancer treatments, in particular surgery; the presence of synergies with other therapies, such as anti-angiogenic agents [Loges et al. 2009]; the possibility that β-blocker exposure is associated with site-specific inhibition of metastasis; and whether associations vary by degree of hypertension.

β-Adrenergic receptor antagonists in breast cancer: clinical studies

There are at least three phase II clinical studies currently assessing the safety and efficacy of β-blockers in breast, colorectal and ovarian cancers [ClinicalTrials.gov identifiers: NCT00502684, NCT00888797 and NCT01308944]. In the breast study, 460 women with stage I/II breast cancer undergoing surgery are being randomized in a double-blind fashion to receive either propranolol (80 mg/day) and etodolac (nonsteroidal anti-inflammatory drug) or placebo from 2 days before to 3 days after surgery. In addition to laboratory studies and safety data, 5-year disease recurrence will be assessed. The planned colorectal cancer study follows a similar design to this. In the ovarian cancer study, 25 women with stage I–IV invasive epithelial ovarian cancer, primary peritoneal carcinoma or fallopian tube cancer will receive propranolol (80 mg/day) from 2 days before surgery and continue treatment for the duration of postoperative chemotherapy. The study’s primary outcome will be safety, but progression-free survival rates and biomarkers of response will also be assessed as secondary outcomes.

Conclusion

Overall, the results from preclinical and pharmacoepidemiological studies support the suggestion that β-blockers could provide a clinical benefit in breast cancer through inhibition of the prometastatic effects of β-AR signalling on tumour immune responses and the tumour microenvironment. To date, however, pharmacoepidemiological studies examining associations between β-blocker use and improved breast cancer outcomes have been limited in sample size. Larger observational studies will enable subgroup analyses to be undertaken so that women most likely to benefit from the addition of a β-blocker to their breast cancer regimen can be identified. This information can be used to better inform the design of randomized clinical studies to address questions regarding the type of β-blocker, predictive biomarkers or tumour characteristics, appropriate treatment paradigms and, most importantly, efficacy. The results from these randomized studies will be required before targeting of the β-AR signalling pathway can be considered a therapeutic option for patients with breast cancer.

Footnotes

Dr TI Barron’s position is supported by a post-doctoral fellowship from the Health Research Board Ireland.

The authors declare no conflict of interest in preparing this article.

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