Metastasis is the leading causes of death in patients with breast cancer, and standard-of-care chemotherapy is not effective in treating metastasis in all patients. Here we identify propranolol, a non-selective β-adrenergic receptor antagonist or β-blocker, as a treatment that can improve the anti-metastasis effect of doxorubicin, a routinely used chemotherapy.
Doxorubicin alone had little effect on metastasis, while it reduced growth of 4T1.2 primary mammary tumours, a mouse model of aggressive breast cancer. Addition of propranolol to doxorubicin significantly delayed metastasis onset and increased metastasis-free incidence in mice, and these effects were independent of primary tumour burden. Mechanistic studies revealed that doxorubicin increased the content of norepinephrine, an endogenous ligand for β-adrenergic receptors, in the plasma and primary tumour. Additionally, doxorubicin specifically increased Adrb2 mRNA expression in a panel of breast cancer cell lines, without affecting Adrb1 mRNA expression, which increases the sensitivity of tumour cells to β2AR signalling and enhances tumour cell invasion.
These mechanistic findings identify a novel mechanism of doxorubicin resistance, where doxorubicin induces a norepinephrine-rich tumour microenvironment and sensitises tumour cells to pro-metastatic β2AR signalling. These studies identify propranolol as a novel anti-metastasis drug that may be safely used to enhance the efficacy of doxorubicin. We are currently evaluating the clinical validity of these findings in randomised clinical trials in cancer patients.