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Background The association between use of β-blockers and breast cancer (BC) prognosis has been investigated in several observational studies, with conflicting results. We performed a nationwide cohort study and a meta-analysis to investigate the association, and assess if it varied between molecular subtypes of BC. Methods We identified women aged ≥50 years with BC diagnosed between 2004 and 2018 in Norway. We used Cox regression models to estimate the association between β-blocker use at diagnosis and BC-specific survival, overall and by molecular subtype. We performed a meta-analysis of observational studies that reported molecular subtype-specific estimates of this association. Results We included 30,060 women, of which 4461 (15%) used β-blockers. After a median follow-up of 5.1 years, 2826 (9%) died of BC. Overall, β-blocker use was not associated with BC-specific survival (hazard ratio [HR] = 1.07; 95% confidence interval [CI]: 0.97–1.19). We found an association only in triple-negative BC (TNBC) patients (HR = 0.66; 95% CI: 0.47–0.91). This was confirmed in the meta-analysis: β-blocker use was associated with progression/recurrence-free (HR = 0.58; 95% CI: 0.38–0.89) and BC-specific survival (HR = 0.74; 95% CI: 0.55–1.00) in TNBC patients only. Conclusion In our cohort of BC patients and in the meta-analysis, β-blocker use was associated with prolonged BC-specific survival only in TNBC patients.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Purpose The sympathetic nervous system drives breast cancer progression through β-adrenergic receptor signalling. This discovery has led to the consideration of cardiac β-blocker drugs as novel strategies for anticancer therapies. Carvedilol is a β-blocker used in the management of cardiovascular disorders, anxiety, migraine and chemotherapy-induced cardiotoxicity. However, little is known about how carvedilol affects cancer-related outcomes. Methods To address this, we investigated the effects of carvedilol on breast cancer cell lines, in mouse models of breast cancer and in a large cohort of patients with breast cancer (n = 4014). Results Treatment with carvedilol blocked the effects of sympathetic nervous system activation, reducing primary tumour growth and metastasis in a mouse model of breast cancer and preventing invasion by breast cancer cell lines. A retrospective analysis found that women using carvedilol at breast cancer diagnosis (n = 136) had reduced breast cancer-specific mortality compared with women who did not (n = 3878) (5-year cumulative incidence of breast cancer deaths: 3.1% versus 5.7%; p = 0.024 and 0.076 from univariate and multivariable analyses, respectively) after a median follow-up of 5.5 years. Conclusions These findings provide a rationale to further explore the use of the β-blocker carvedilol as a novel strategy to slow cancer progression.

BackgroundCancer-related cognitive impairment (CRCI) has been reported in cancer survivors 20 years or more after cancer treatment, and has been associated with sustained increases in circulating inflammatory biomarkers. One of the major risk factors for CRCI is chemotherapy, and preclinical studies typically examine the impact of chemotherapy in cancer naïve mice to evaluate potential mechanisms However, clinical evaluation of the long-term effects of chemotherapy cannot avoid the potential cumulative impact of preceding factors on the brain including the cancer itself and cancer surgery. MethodsTo evaluate the cumulative impact of cancer-related factors on cognitive impairment and hippocampal cytokine expression, we evaluated the effect of paclitaxel chemotherapy vs. placebo on a background of 67NR mammary carcinoma and surgical resection of the primary tumour in mice. Memory was assessed using the Y maze test and novel object/novel place recognition test. Changes in hippocampal pro-inflammatory and anti-inflammatory cytokines, microglia and neuron markers were assessed using qRT-PCR. Results Cancer and cancer surgery was sufficient to induce long-term memory impairment and sustained increases in hippocampal pro-inflammatory cytokines. Paclitaxel prolonged spatial memory impairment in the Y maze test and exacerbated hippocampal Il6 and Tnfa mRNA expression compared with placebo treatment. ConclusionsThese findings suggest that cancer and cancer surgery can sensitise the brain to an exaggerated neuroinflammatory response to chemotherapy, and may contribute to sustained chemotherapy-induced cognitive impairment observed in cancer survivors.

Cancer patients with non-central nervous system tumors often suffer from cognitive impairment. While chemotherapy has long been attributed as the cause of these memory, learning and concentration difficulties, we recently observed cognitive impairment in cancer patients prior to treatment. This suggests the cancer alone may be sufficient to induce cognitive impairment, however the mechanisms are unknown. Here, we show that we can experimentally replicate the clinical phenomenon of cancer-associated cognitive impairment and we identify inflammation as a causal mechanism. We demonstrate that a peripheral tumor is sufficient to induce memory loss. Using an othotopic mouse model of breast cancer, we found that mice with 4T1.2 or EO771 mammary tumors had significantly poorer memory than mice without tumors. Memory impairment was independent of cancer-induced sickness behavior, which was only observed during the later stage of cancer progression in mice with high metastatic burden. Tumor-secreted factors were sufficient to induce memory impairment and pro-inflammatory cytokines were elevated in the plasma of tumor-bearing mice. Oral treatment with low-dose aspirin completely blocked tumor-induced memory impairment without affecting tumor-induced sickness or tumor growth, demonstrating a causal role for inflammation in cognitive impairment. These findings suggest that anti-inflammatories may be a safe and readily translatable strategy that could be used to prevent cancer-associated cognitive impairment in patients.

Chronic stress accelerates metastasis – the main cause of death in cancer patients – through the activation of β-adrenoceptors (βARs). We have previously shown that β2AR signaling in MDA-MB-231HM breast cancer cells, facilitates invadopodia formation and invasion in vitro. However, in the tumor microenvironment where many stromal cells also express βAR, the role of β2AR signaling in tumor cells in metastasis is unclear. Therefore, to investigate the contribution of β2AR signaling in tumor cells to metastasis in vivo, we used RNA interference to generate MDA-MB-231HM breast cancer cells that are deficient in β2AR. β2AR knockdown in tumor cells reduced the proportion of cells with a mesenchymal-like morphology and, as expected, reduced tumor cell invasion in vitro. Conversely, overexpression of β2AR in low metastatic MCF-7 breast cancer cells induced an invasive phenotype. Importantly, we found that knockdown of β2AR in tumor cells significantly reduced the impact of stress on metastasis in vivo. These findings highlight a crucial role for β2AR tumor cell signaling in the adverse effects of stress on metastasis, and indicate that it may be necessary to block β2AR on tumor cells to fully control metastatic progression.

The tumor microenvironment is known to play a pivotal role in driving cancer progression and governing response to therapy. This is of significance in pancreatic cancer where the unique pancreatic tumor microenvironment, characterized by its pronounced desmoplasia and fibrosis, drives early stages of tumor progression and dissemination, and contributes to its associated low survival rates. Several molecular factors that regulate interactions between pancreatic tumors and their surrounding stroma are beginning to be identified. Yet broader physiological factors that influence these interactions remain unclear. Here, we discuss a series of preclinical and mechanistic studies that highlight the important role chronic stress plays as a physiological regulator of neural-tumor interactions in driving the progression of pancreatic cancer. These studies propose several approaches to target stress signaling via the β-adrenergic signaling pathway in order to slow pancreatic tumor growth and metastasis. They also provide evidence to support the use of β-blockers as a novel therapeutic intervention to complement current clinical strategies to improve cancer outcome in patients with pancreatic cancer.

Inflammation may contribute to the adverse effects of chemotherapy on cognition and affect, (chemobrain). Here, we tested the hypothesis that the chemoagent paclitaxel induces sustained changes in cognitive and affective-like behavior that correspond with increased inflammation in mice. We treated BALB/c mice with paclitaxel (10 mg/kg i.p.) or vehicle every second day over two weeks. We conducted a battery of tests to examine memory, sickness and affect at 24 h and 14 days after treatment. Paclitaxel significantly reduced memory and increased depression-like behavior as measured by novel object recognition and sucrose preference at both timepoints. These effects were independent of sickness. Analysis of inflammation by ELISA showed no evidence of inflammation at 24 h, suggesting that inflammation may not be responsible. Cytotoxic effects on the brain may be responsible for these immediate behavioral changes. We confirmed that paclitaxel crosses the blood-brain barrier by HPLC, and are performing untargeted metabolomics analyses on brain tissue to examine widespread functional changes in brain metabolism and neurochemistry. Inflammation was apparent at 2 weeks, and we are confirming that inflammation is also elevated in the brain at this timepoint. These findings suggest that inflammation may be responsible for the later paclitaxel-induced cognitive and affective symptoms but cannot be responsible for the immediate effects of paclitaxel on cognition and depression-like behavior.