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Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer, with limited treatment options. Studies have suggested that therapeutic blockade of β2-adrenoceptors might enhance TNBC outcomes. To explore this, Chang et al. retrospectively evaluated cancer relapse and survival in a cohort of 1,135 women with nonmetastatic TNBC and found beta blocker use to be associated with a reduced risk of metastasis relapse in patients that had been treated with anthracycline-containing chemotherapy regimens. Similarly, in TNBC mouse xenograft models, administration of the beta-blocker propranolol during treatment with the anthracycline doxorubicin, delayed the onset of spontaneous metastasis and reduced the progression of established metastasis. Mechanistic analysis in preclinical models and patient TNBC tumour biopsies revealed that anthracycline drugs elevate sympathetic nervous system (SNS) signaling by increasing sympathetic innervation in tumours and by enhancing tumour cell response to the SNS by up-regulating β2AR expression. In xenograft mouse models, inhibition of sympathetic neural signaling in breast tumours using 6-hydroxydopamine or genetic deletion of the β2-adrenoceptor in tumour cells enhanced the therapeutic efficacy of doxorubicin on metastasis.
