β-Adrenoceptor Activation in Breast MCF-10A Cells Induces a Pattern of Catecholamine Production Similar to that of Tumorigenic MCF-7 Cells

Abstract

Adrenaline, which participates in the neuroendocrine response that occurs during stress and perimenopause, may be tumorigenic. This exploratory study aimed at investigating whether non-tumorigenic and tumorigenic human breast epithelial cell lines are able to synthesize adrenaline. The study was carried out in non-tumorigenic (MCF-10A) and tumorigenic (MCF-7) human breast cell lines. Expression of enzymes involved in adrenaline synthesis was characterized by RT-qPCR, immunocytochemistry and western blot. Catecholamines and analogue compounds were quantified by HPLC-ECD. Functional assessment of the impact of drugs on cells’ tumorigenic potential was assessed by determination of cell viability and clonogenic ability. Both MCF-10A and MCF-7 cells produce catecholamines, but the capacity to produce adrenaline is lower in MCF-10A cells. β-adrenoceptor activation increases the capacity of MCF-10A cells to produce adrenaline and favor both cell viability and colony formation. It is concluded that exposure of human breast epithelial cells to β-adrenoceptor agonists increases cell proliferation and the capacity to produce adrenaline, creating an autocrine potential to spread these adrenergic effects in a feed-forward loop. It is conceivable that these effects are related to tumorigenesis, bringing a new perspective to understand the claimed anticancer effects of propranolol and the increase in breast cancer incidence caused by stress or during perimenopause.

Serotonin after β-Adrenoreceptors’ Exposition: New Approaches for Personalized Data in Breast Cancer Cells

“…The observation and morphological analysis of the cells treated with the different concentrations of this established antineoplastic agent was also carried out (Figure 5). Analyzing the obtained curve, it is possible to conclude that, in agreement with our previous work [15], with the seeding density of 2.3 × 10 4 cells/mL (4600 cells/well), the cells remained in the exponential growth phase during the experiments, ensuring the stability and viability of MCF-7 cells.…”

“…With Recently, our group reported that three drugs that interact with the adrenergic system (ICI 118,551, isoprenaline, and propranolol; Table 1) influence the proliferation of breast cells (tumorigenic MCF-7 cells) and their ability to produce adrenaline. It was observed that these cells have the potential to synthesize and release adrenaline, influenced by the exposure to agonists/antagonists of β-adrenoreceptors [15]. Indeed, evidence from the literature suggests the presence of β-adrenoreceptors in cancer cells, important for different processes of initiation and progression of the disease [16].…”

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

“…In addition to the adrenergic modulation exerted by neuronal and plasma catecholamines, the breast tissue may also be exposed to catecholamines produced in the breast microenvironment by nonneuroendocrine cells. It has been shown that breast cells may also produce noradrenaline and acquisition of a tumorigenic phenotype may increase the capacity of breast cells to go further in the catecholamine biosynthetic pathway, increasing the capacity to transform noradrenaline in adrenaline, as recently reported by our research group (Amaro et al, 2020). These locally produced catecholamines may potentiate the adrenergic capacity to promote carcinogenesis creating an adrenergic influence of the tumor autonomous from catecholamines produced elsewhere.…”

“…In addition to this neuronal adrenergic influence, blood born adrenaline and noradrenaline were also reported to inhibit the immune system activity (Ben‐Eliyahu et al, 2000), altering immune cell redistribution and function in several compartments including the spleen, lymph nodes and blood (Andersen et al, 1998; Ben‐Eliyahu et al, 2000; Mohammadpour et al, 2019; Shaashua et al, 2017; Shakhar & Ben‐Eliyahu, 1998; L. Zhou et al, 2016). The adrenergic modulation of the immune response to breast cancer can even be more oriented than previously expected, having in mind the recent finding that cancer cells may produce locally adrenaline, making the adrenergic contribution for the immunosuppressive tumor microenvironment even more efficient and less dependent from SNS stimulation and from plasma catecholamines (Amaro et al, 2020).…”

“…Expression of several adrenergic receptors from the α 1 , α 2 and/or β subtypes was observed in a number of preclinical models of breast cancer and in human tissues of breast cancers (Amaro et al, 2020; Y. Du et al, 2014; Gruet et al, 2020; Perez Pinero et al, 2012; Powe et al, 2011; Vazquez et al, 2006).…”