تاثیر مهار نیتریک اکسید سنتاز بر توقف تسریع متاستاز سرطان سینه
Abstract
1- Introduction
2- Methods
3- Results
4- Discussion
References
Abstract
Stress hormones have been shown to be important mediators in driving malignant growth and reducing treatment efficacy in breast cancer. Glucocorticoids can induce DNA damage through an inducible nitric oxide synthase (iNOS) mediated pathway to increase levels of nitric oxide (NO). Using an immune competent mouse breast cancer model and 66CL4 breast cancer cells we identified a novel role of NOS inhibition to reduce stress-induced breast cancer metastasis. On a mechanistic level we show that the glucocorticoid cortisol induces expression of keys genes associated with angiogenesis, as well as pro-tumourigenic immunomodulation. Transcriptomics analysis confirmed that in the lungs of tumour-bearing mice, stress significantly enriched pathways associated with tumourigenesis, some of which could be regulated with NOS inhibition. These results demonstrate the detrimental involvement of NOS in stress hormone signalling, and the potential future benefits of NOS inhibition in highly stressed patients.
Introduction
Psychological stress induces an increase in the circulating levels of stress hormones, including the glucocorticoid cortisol [1]. Epidemiological evidence has associated negative psychosocial factors, including chronic stress, with increased incidence and poorer survival in breast cancer patients [2]. Furthermore, multiple studies have linked psychological stress with biological processes involved in metastasis [3–5], findings of particular importance since the primary cause of breast cancer-related death is metastatic spread [6]. Glucocorticoid signalling, mediated through the glucocorticoid receptor (GR), has been shown to promote tumourigenesis and drug-resistance in triple negative breast cancer (TNBC) [7], and increases in expression of GR in breast tumours have been correlated with decreased survival [8]. GR antagonism has also previously been shown to induce apoptosis and, in combination with conventional chemotherapies, reduce tumour size in models of TNBC [9]. We have previously explored the mechanistic actions of psychological stress in breast cancer, and shown that stress hormone exposure can induce DNA damage in breast cancer through the generation of reactive oxygen and nitrogen species (ROS/RNS). We have also previously shown that glucocorticoids mediate a non-genomic effect on inducible nitric oxide synthase (iNOS), the enzyme that generates NO, and increase nitric oxide (NO) signalling in breast cancer cells [10]. Although iNOS is expressed in both ER+ and ER-breast cancers [11,12], expression of iNOS has been found to correlate with tumour progression and poor survival in basal-like breast cancers [13,14], indicating that NO activity may drive malignant growth and spread. As such, iNOS represents a potential target to abrogate the detrimental effects of psychological stress hormone signalling. Nitric oxide (NO) is an important signalling molecule modulating a range of functions within the cell, however the role of NO in tumour biology is complex and multifaceted [15]. Aspects of tumourigenic transformation can be driven by prolonged inflammation and exposure to high concentrations of NO, resulting in an increase in oxidative stress and subsequent DNA damage [16]. It is thought that NO may also be capable of driving transformation through the induction of angiogenesis and migration [17]. The highest concentrations of NO are produced by iNOS, and expression of iNOS has been shown to be positively correlated with tumour grade, stage and metastasis in breast cancer [11,18–20]. Several studies have shown that induction of iNOS expression in tumour cells promotes an increase in angiogenesis, and subsequently an increase in invasiveness and progression [16,21,22].