Evidence accumulated over the last 20 years indicates that beta-blockers are beneficial or perhaps even life-saving in early stage breast cancer (BC). Importantly, beta-blockers reduce mortality and have a more pronounced prognostic effect mainly in triple-negative breast cancer (TNBC), the most aggressive type of BC.
Most BC patients present with hyperactive sympathetic nervous system (SNS). Here we discuss the probability that in TNBC patients this feature is exaggerated, i.e. their SNS activity is even more hyperactivated as compared to other BC patients. In particular, this also may suggest that beta-blockers are a more important adjunct in TNBC as compared to in other molecular BC subtypes.
Generally, research and clinical data, mostly from the last 10-15 years, strongly indicate that the SNS innervation and a hyperactive SNS via activation of the β2-adrenergic receptors (β2-ARs) contributes to tumor-related immunosuppression and by extension to tumor proliferation, growth and metastasis. Below is a summary of the systematic reviews and meta-analysis data. Positive results and conclusion are highlighted in red; whereas negative results or conclusion are marked with grey.
Summary of Systematic Reviews & Meta-Analysis Data
2016, Int J Cancer,Meta-Analysis:Significant improvement in BC specific survival in patients treated with beta-blockers at the time of BC diagnosis; borderline significant improvement in disease free survival.
2016, Eur J Cancer Prev,Meta-Analysis: Only breast cancer patients who used β blockers after diagnosis had a prolonged overall survival. The average effect of β-blocker use after diagnosis but not before diagnosis is beneficial for the survival.
2016, Breast Cancer Res,Pooled Analysis/Meta-Analysis:The use of propranolol or non-selective beta-blockers was not associated with improved survival.
2017, Oncotarget,Meta-Analysis:Non-selective β-blockers, but not selective β-blockers, reduced tumor proliferation by 66% in early stage breast cancer.
2017, Oncology,Meta-Analysis: Beta-blockers were not beneficialregarding overall deaths (ODs), cancer-specific deaths or recurrences.
2019, Neoplasma, Systematic Review: A beneficial effect of beta-blockers in TNBC treatment.
2020, Biosci Rep,Meta-Analysis: Observational studies do not support a significant association between beta-blockers use and improved prognosis.
2021 Front Pharmacol,Meta-Analysis: Calcium channel blockers, beta-blockers and diureticsincrease the risk of breast cancer.
2021, ESMO Open, Meta-Analysis: Beta-blocker use was associated with a longer recurrence-free survival in patients with early-stage breast cancer; more pronounced effect observed in those with triple-negative disease.
2022, Br J Cancer, Meta-Analysis: In the cohort of BC patients and in the meta-analysis, the beta-blocker use was associated with prolonged BC-specific survival only in TNBC patients.
The case with TNBC
Apart from the 2019, Neoplasma, 2021, ESMO Open and the 2022, Br J Cancerstudy discussed above, another 5 studies address the use of beta-blockers in TNBC:
Thus, in summary, 8 Systematic Reviews and Meta-Analysis, out of a total 12, support the use of beta-blockers in breast cancer; and, all recent 7 TNBC-related studies support the beta-blockers use in TNBC. This overall suggests that the beta-blockers most likely prevent or block, at least to some extent, the effects of the hyperactive SNS that contributes to a tumor-related immunosuppression and the BC tumor proliferation, growth and metastasis.
I. Why this might be the case
Lymphoid organs and tumor tissues, including BC, receive dense sympathetic innervation
Thus, the immune system is tuned by locally released norepinephrine (NE, or noradrenaline) or circulating epinephrine (EPI, or adrenaline) secreted by the adrenal medulla. Hence, the SNS and its end-products, catecholamines (CAs), provide a major integrative and regulatory pathway between the brain and the immune system.
On the other hand, cells localized in the tumor microenvironment release nerve growth factors that attract new sympathetic nerves into the cancer tissue. Therefore, this promotes a vicious nerve-tumor feedback loop that potentiates tumor growth. In keeping with this, increased density of sympathetic nerves is connected with poorer prognosis of cancer disease.
Immune cells and BC tumor cells express beta-adrenergic receptors (β-ARs)
One study shows that the specific order of receptor density is NK cells > CD14+ monocytes > Tcytotoxic (Tc) ≥ B cells > Th cells, whereas another study demonstrates slightly different order NK cells > Tc ≥ B cells ≥ monocytes > Th cells.
Of note, it appears that NK cells, which are critical for anti-tumor immunity, express the highest β-ARs numbers. Lymphocyte and NK cell β-ARs belong to the β2-ARs subtype, and the receptor number ranges from about 4000 receptors/cell for NK and B cells, approximately 1800 receptors for Tc, to between 200 and 750 binding sites for Th cells.
Tumor cells originating from various tissues express adrenergic receptors, especially the β2-subtype. In vitro studies have shown that administration of β-adrenergic agonist stimulates tumor cell growth, whereas administration of β-blockers binding on β2-subtype significantly reduce cell growth. This subtype of adrenergic receptors is expressed also on breast cancer cells.
Suppression of Cellular Immunity &Upregulation of TGF-β, IL-6, IL-8 and IL-10
Selective suppression of Th1-dependent cellular immunity
In the past, it was believed that the two major catecholamines (CAs) EPI and NE, similar to glucocorticoids, are causing ‘general immunosuppression’. Recent evidence, however, indicates that both CAs and glucocorticoids, at levels that can be achieved during stress, influence the immune response in a less uniform way.
Under physiological conditions, this may protect the organism from the detrimental effects of pro-inflammatory cytokines and other products of activated macrophages (e.g. in autoimmunity). However, conditions with hyperactive SNS including hyperactive stress system may contribute to immunosuppression, and specifically, to a selective failure of cellular immunity.
This might be particularly relevant to cancer, where cellular immunity is the critical immune branch responsible for tumor protection and surveillance.
Figure 2.Epinephrine and norepinephrine suppress NK cells and NK-mediated Tc and macrophage activation. Abbreviations: IFN, interferon; Ma, macrophage, NK, Natural killer cell; TC, a cytotoxic T cell (also known as cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell); TNF, tumor necrosis factor.
Both, in vitro, EPI and isoproterenol (β-agonist), or in vivo, β-receptor agonists administration result in suppression of NK activity. Central administration of corticotropin-releasing hormone (CRH), which is known to increase the sympathetic autonomic outflow, is accompanied by decreased NK activity in the periphery. Interestingly, in patients with heart failure, a condition characterized by chronically high levels of plasma NE, these levels correlate with anergy in the cytotoxicity of circulating NK cells (cf. Elenkov et al. 2000). Moreover, several lines of evidence suggest that stress, which is accompanied by increased levels of peripheral CAs, also inhibits NK cell activity, an effect that is mediated mainly by the CRH–SNS axis.
It appears that NK cells are the most ‘sensitive’ cells to the suppressive effect of stress, and not surprisingly, in the past, NK cell activity has been used as a bona fide index of stress-induced suppression of cellular immunity (for review see M. Irwin, 1994).
The potent suppressive effect of CAs on NK cell activity is probably due to the above-discussed fact that NK cells possess the highest number of β2-ARs among lymphoid cells. Thus, overall, the NK cells’ ‘supersensitivity’ to CA effects is perhaps another major factor contributing to the suppression of cellular immunity and perhaps its complete failure in cancer.
Upregulation of TGF-β, IL-6, IL-8 and IL-10 – relevance to tumorigenesis
Catecholamines potentiate the production of IL-8 by monocytes and epithelial cells. Also, EPI promotes IL-8 production by human leukocytes via an indirect effect on platelets. In fact, as shown by Kaplanski et al., activated platelets are able to induce endothelial secretion of IL-8.
Of note, akin to normal tissue, cancer tissue is proposed to be organized in a hierarchical manner, which may underpin the cellular heterogeneity of cancers. At the apex lies the tumor-initiating or cancer stem-like cell (CSC), so called because these cells share key stem cell properties of their normal tissue counterparts. IL-8 is overexpressed in breast cancer and promotes breast cancer initiation and progression, and recent evidence indicates that this cytokine is a key regulator of CSC activity.
The special case of the myeloid-derived suppressor cells (MDSCs)
Myeloid-derived suppressor cells (MDSC), a class of immune suppressor cells (≤1% of circulating cells), are characterized by the ability to suppress immune responses and expand during cancer, infection, and inflammatory diseases. In fact, MDSCs are pathologically activated neutrophils and monocytes with potent immunosuppressive activity.
Studies in the 1970s have highlighted these systematically expanded and pathologically activated immature myeloid cells in tumor-bearing hosts. Based on their myeloid origin and immunosuppressive potency, these cells were termed MDSCs in 2007. These cells are now known to accumulate in patients with cancer and their numbers seem to correlate with tumor burden. Of note, MDSCs are a major source of IL-10 in the tumor-bearing host and, accordingly, the frequency of MDSCs is correlated with the IL-10 level in peripheral blood of cancer patients.
It appears that stress upregulates MDSCs in breast cancer in mice. Furthermore, chronic psychosocial stress not only increases the number of MDSC and Treg cells, but in the case of MDSC also enhances their suppressive capacity. A recent 2021 study indicates that chronic stress pre-exposure contributed to MDSC elevation and facilitated breast cancer metastasis in tumor-bearing mice. In experimental settings, data indicated that chronic stress may accumulate MDSCs via activation of β-adrenergic signaling and IL-6/STAT3 pathway, thereby promoting breast carcinoma metastasis.
Tumorigenic Effects via β-Adrenergic Receptors – direct effect of these receptors, locally, on tumor proliferation and metastasis
Activation of β-adrenergic receptors expressed by cells localized in tumor microenvironment affects hallmarks of cancer, including:
sustaining proliferative signalling
evading growth suppressors
resisting cell death
enabling replicative immortality
activating invasion and metastasis
reprogramming of energy metabolism and
evading immune destruction.
These effects are mediated mostly via β-adrenergic receptors expressed on cancer cells. The stimulating effect of activated β-adrenergic receptors on cancer growth and metastasis is mediated by increased gene expression of TGF-β, vascular endothelial factor (VEGF), arginase-1, macrophage colony-stimulating factor (M-CSF), cyclooxygenase 2 (COX-2), matrix metalloproteinase-9 (MMP-9) and IFN-β. In addition , the β-adrenergic system can affect cancer biology by promoting tumor invasion, angiogenesis, and ultimately increasing metastatic potential (cf. T.I. Barron et al. 2011).
Stress affects immunity and tumors directly, predominantly via β2-adrenergic receptors
There are an abundance of data and literature about the role of psychological stress and its effects on cancer, including BC, but a detailed review is beyond the scope of the present work.
The stress-induced release of hypothalamic CRH leads ultimately to peripheral release of glucocorticoids (cortisol) and CAs. Cortisol (released from the adrenal cortex) and EPI (adrenaline, from the adrenal medulla) represent the two major stress hormones.
NE and neuropeptide Y (NPY) represent the two major stress mediators. These two neurotransmitters are (co)released by sympathetic nerve terminals/endings. NPY release may be a less-than-appreciated stress factor, but it may play an important role in more intense stress or chronic stress conditions.
The major catecholamines epinephrine and norepinephrine are the end products of SNS activation. As SNS represents one of the two major peripheral limbs of the stress system, stress may affect immunity and tumors mostly via β2-adrenergic receptors. Effects of α-adrenergic, or glucocorticoid and NPY receptors are not discussed here. However, it is necessary to note that experimental and clinical data show involvement of these hormones and their receptors in the processes related to cancer growth and metastasis, as well.
High rates of obesity and a prevalence of African-American women in TNBC patients; Presence of sympathetic overdrive in this condition?
TNBC is characterized by the lack of estrogen and progesterone receptor expression and lacks HER2 overexpression or gene amplification. It accounts for 10–15% of incident breast cancers and carries the worst prognosis. TNBC is overrepresented among Black and pre-menopausal women.
II. What are the reasons that may cause inconsistency in results about the use of beta-blockers in BC?
As mentioned previously, 8 systematic reviews and meta-analyses, out of a total 12, support the use of beta-blockers in breast cancer. Also, many clinical studies indicate a beneficial effect of beta-blockers in BC, but several other studies did not. Moreover, a 2021 study reports an increased risk of breast cancer associated with the use of β1 selective blockers. This raises the question what might be the reason for this inconsistency. Below we summarize some major reasons that may contribute to these differences:
The type of beta-blockers: The use of non-selective beta-blockers versus selective beta-blockers.
In many studies no distinction was made between the use of non-selective beta-blockers versus selective beta-blockers. β1-blockers, mostly used in hypertension, and now in BC, are perhaps not effective in BC, for the simple reason that immune cells, as well as the tumor cells and tissue(s) express mostly the β2-adrenergic receptor.
Many clinical studies showed that treatment with selective β1-blockers had no effect on survival of women with BC, in contrast to propranolol (non-selective β-blocker). Studies comparing β1 and β2 receptor antagonists have demonstrated that the effects of β-adrenergic signaling on tumor progression and metastasis are inhibited by β2 antagonists but not β1 antagonists.
The case of propranolol
In 2011 Barron et al. reported that women diagnosed with Stage I – IV BC, taking propranolol in the year before breast cancer diagnosis had a reduced incidence of locally invasive (T4) or metastatic (N2/N3/M1) tumours. However, a 2011 pooled European analysis found no evidence for a protective effect of propranolol or beta-blockers in general – although the study did not assess outcomes by stage or primary vs. metastatic disease. A 2017 retrospective cross-sectional study reports that in early stage breast cancer non-selective β-blockers reduce tumor proliferation by 66%. Also, in 2017 Shaashua et al. found that propranolol and the COX-2 inhibitor etodolac inhibit multiple cellular and molecular pathways related to metastasis and disease recurrence in early-stage BC. In 2019 Montoya et al. reported that propranolol reduced the proliferative index of a stage III breast tumor by 2.7-fold, whereas Hiller et al., in 2020, demonstrated that beta-blockade reduces biomarkers associated with metastatic potential. A 2021 meta-analysis, included data from 13 studies with more than 103 000 patients with early-stage breast cancer, showed that the use of beta-blockers was associated with a longer recurrence-free survival (RFS); with a more pronounced effect observed in those with triple-negative disease. And, in 2021, Murugan S, B Rousseau and D Sarkar found that the combined treatments of propranolol and the µ-opioid receptor antagonist naltrexone produce impressive antitumor effects in a preclinical breast cancer model.
Beta-blockers, and particularly the non-selective beta-blockers, exert a beneficial effect in cancer patients with exaggerated activity of the SNS.
In fact, this is the case of TNBC (see above), where exaggerated SNS activity is most likely coupled with the high expression of β-adrenergic receptors in TNBC tumor cells. Social isolation or low socioeconomic status, also inducers of SNS activation, could thus also play a role in tumor cell proliferation.
Herein, we have compiled recent evidence indicating that the hyperactive SNS in BC patients may drive and promote tumor proliferation, growth and metastasis. These features appear to be extremely amplified in TNBC patients. In TNBC, the SNS overdrive is most likely coupled with an overexpression of β-adrenergic receptors in tumor cells, providing the micro and macro-environment for the growth of this very invasive and metastatic BC subtype.
The hyperactive SNS, via activation of β2-adrenergic receptors mediates substantial:
Suppression of cellular immunity, and particularly NK and Th1 cells.
Upregulation of immunosuppressive Treg cells.
Upregulation of TGF-β, IL-6, IL-8 and IL-10 immunosuppressive cytokines.
Upregulation of immunosuppressive MDSCs cells.
Direct effect of β-adrenergic receptors on tumor proliferation and metastasis.
Several questions remain.
What is the best choice of beta blocker and the optimal dosing? Just for propranolol, there are over 20 active clinical trials in different cancers as per a 2018 editorial. These clinical trials will give more definitive answers regarding safety and effectiveness of beta-blockers in cancer, including BC.
What are the factors that drive hyperactive SNS in BC, and predominantly in TNBC? Is this, in some cases related to some forms of a primary hyperactive SNS, or it is simply related to co-morbidities such as obesity, metabolic syndrome, etc.? Along these lines – what is the role of the recent epidemics of obesity and/or the role of psychological stress?
In conclusion, clearly beta-blockers hold therapeutic potential, and at least for propranolol the potential for repurposing is being actively pursued in multiple clinical trials. A nuanced understanding of the role of the SNS in cancer and particularly TNBC may contribute to readily accessible and inexpensive adjunctive therapeutic strategies for cancer patients.
Boris Mravec, PhD – Institute of Physiology, Faculty of Medicine, Comenius University in Bratislava, Slovakia Biomedical Research Center, Institute of Experimental Endocrinology, Slovak Academy of Sciences, Bratislava, Slovakia; email@example.com;
Dimana Dimitrova Broadway, MD – Center for Immuno-Oncology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. USA. Disclaimer:Dr. Dimitrova Broadway contributed to this article in her personal capacity. Any views expressed are her own and do not necessarily represent the views of the National Institutes of Health, the U.S. Public Health Service, or the United States Government.
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