Stress in Metastatic Breast Cancer: To the Bone and Beyond

Abstract

Breast cancer (BRCA) remains as one the most prevalent cancers diagnosed in industrialised countries. Although the overall survival rate is high, the dissemination of BRCA cells to distant organs correlates with a significantly poor prognosis. This is due to the fact that there are no efficient therapeutic strategies designed to overcome the progression of the metastasis. Over the past decade, critical associations between stress and the prevalence of BRCA metastases were uncovered. Chronic stress and the concomitant sympathetic hyperactivation have been shown to accelerate the progression of the disease and the metastases incidence, specifically to the bone. In this review, we provide a summary of the sympathetic profile on BRCA. Additionally, the current knowledge regarding the sympathetic hyperactivity, and the underlying adrenergic signalling pathways, involved on the development of BRCA metastasis to distant organs (i.e., bone, lung, liver and brain) will be revealed. Since bone is a preferential target site for BRCA metastases, greater emphasis will be given to the contribution of α2- and β-adrenergic signalling in BRCA bone tropism and the occurrence of osteolytic lesions.

Keywords: adrenergic receptors; breast cancer; metastasis; stress; sympathetic nervous system.

Figure 1

Intrinsic characteristics of each BRCA subtype, in terms of receptor expression profile, prognosis, treatment, percentage of incidence and metastasis distribution. Abbreviations: BRCA—breast cancer; CK—cytokeratin; ECM—epithelial to mesenchymal transition; ER—oestrogen receptor; ERBB2—human epidermal growth factor receptor-type 2; HER2—human epidermal growth factor 2; Ki 67—antigen Ki-67; PR—progesterone receptor; TNBC—triple-negative breast cancer.

Figure 2

A brief summary of the established correlations between stress, BRCA and metastases. In a stress situation, catecholamines (NE and E) are released by the sympathetic fibres and sympathoadrenal system. These catecholamines stimulate the activation of adrenergic receptors, locally in BRCA primary tissue and also by affecting the BRCA metastatic organs. Abbreviations: ADR—adrenergic receptor; BRCA—breast cancer; E—epinephrine; HER2—human epidermal growth factor 2; NE—norepinephrine; RANKL—receptor activator of NF-κB ligand; TNBC—triple-negative breast cancer; VEGF—vascular endothelial growth factor.