Contribution of adrenergic mechanisms for the stress‐induced breast cancer carcinogenesis

Breast cancer is the most common and deadliest type of cancer in women. Stress exposure has been associated with carcinogenesis and the stress released neurotransmitters, noradrenaline and adrenaline, and their cognate receptors, can participate in the carcinogenesis process, either by regulating tumor microenvironment or by promoting systemic changes. This work intends to provide an overview of the research done in this area and try to unravel the role of adrenergic ligands in the context of breast carcinogenesis. In the initiation phase, adrenergic signaling may favor neoplastic transformation of breast epithelial cells whereas, during cancer progression, may favor the metastatic potential of breast cancer cells. Additionally, adrenergic signaling can alter the function and activity of other cells present in the tumor microenvironment towards a protumor phenotype, namely macrophages, fibroblasts, and by altering adipocyte's function. Adrenergic signaling also promotes angiogenesis and lymphangiogenesis and, systemically, may induce the formation of preneoplastic niches, cancer-associated cachexia and alterations in the immune system which contribute for the loss of quality of life of breast cancer patients and their capacity to fight cancer. Most studies points to a major contribution of β2 -adrenoceptor activated pathways on these effects. The current knowledge of the mechanistic pathways activated by β2 -adrenoceptors in physiology and pathophysiology, the availability of selective drugs approved for clinical use and a deeper knowledge of the basic cellular and molecular pathways by which adrenergic stimulation may influence cancer initiation and progression, opens the possibility to use new therapeutic alternatives to improve efficacy of breast cancer treatments.