Profiling the Adrenergic System in Breast Cancer and the Development of Metastasis

SIMPLE SUMMARY: A cancer diagnosis can be a highly stressful experience and breast cancer (BC) patients are at a higher risk of suffering from depression and chronic stress. Thus, the activation of the adrenergic system might negatively impact the disease’s progression. In this study, we propose to perform a comprehensive study on the adrenergic profile in BC and correlate it with the occurrence of metastasis. Our analysis showed that BC patients are indeed under the control of the sympathetic nervous system (SNS), since the circulating levels of catecholamines are elevated in BC patients at all stages of the disease. Metastatic bone biopsies express sympathetic nerve fibers and adrenoreceptors. Moreover, we also observed a pronounced gene expression and the downregulation of adrenoreceptors and catecholamine metabolic enzymes in BC tissues. This downregulation appears to be detrimental for the prognosis of the disease. The evidence gathered will be crucial in the design of new therapeutic approaches targeting SNS in BC. ABSTRACT: Epidemiological studies and preclinical models suggest that chronic stress might accelerate breast cancer (BC) growth and the development of metastasis via sympathetic neural mechanisms. Nevertheless, the role of each adrenergic pathway (α1, α2, and β) in human samples remains poorly depicted. Herein, we propose to characterize the profile of the sympathetic system (e.g., release of catecholamines, expression of catecholamine metabolic enzymes and adrenoreceptors) in BC patients, and ascertain its relevance in the development of distant metastasis. Our results demonstrated that BC patients exhibited increased plasma levels of catecholamines when compared with healthy donors, and this increase was more evident in BC patients with distant metastasis. Our analysis using the BC-TCGA database revealed that the genes coding the most expressed adrenoreceptors in breast tissues (ADRA2A, ADRA2C, and ADRB2, by order of expression) as well as the catecholamine synthesizing (PNMT) and degrading enzyme (MAO-A and MAO-B) genes were downregulated in BC tissues. Importantly, the expression of ADRA2A, ADRA2C, and ADRB2 was correlated with metastatic BC and BC subtypes, and thus the prognosis of the disease. Overall, we gathered evidence that under stressful conditions, both the α2- and β2-signaling pathways might work on a synergetic matter, thus paving the way for the development of new therapeutic approaches.