DNA damage as a result of psychological stress: implications for breast cancer

Accumulating evidence indicates that psychological stress can have deleterious influences on cancer development and progression, but the mechanisms responsible remain unclear. One possible mechanism is suggested by emerging evidence that DNA damage is increased by exposure to stress and stress hormones (for example, cortisol, catecholamines). Possible molecular mechanisms for such effects were the subject of a recent paper by Hara and colleagues, which suggests that chronic stress, through β-adrenergic stimulation, can induce two synergistic pathways that result in accumulation of DNA damage. Herein, we discuss the potential implications of these findings for breast cancer etiology, progression, and treatment response.


Background
Evidence that psychological stress can contribute to the development and progression of cancer has accumulated over the past several decades, but the mechanisms responsible remain obscure [1][2][3][4][5]. A comprehensive metaanalysis of 165 longitudinal studies concluded that psycho social factors are associated with higher incidence, poorer survival and increased mortality [6]. Psychological stress activates the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system, resulting in systemic increases in cortisol and catecholamines. Th e eff ects of catecholamines are mediated by nine distinct αadrenergic and β-adrenergic G-protein-coupled recep tors, which are present on a wide range of cell types, including cancer cells [7].
One underappreciated possible mechanism for stress eff ects on cancer is suggested by emerging evidence that DNA damage is increased by exposure to stress and stress hormones [8,9]. Indeed, a recent report has documented that β-adrenergic stimulation can cause DNA damage suffi cient to promote transformation and tumorigenicity of mouse 3T3 cells [10]. Currently, however, little is known about the molecular pathways responsible for stress-induced DNA damage. A recent report in Nature has provided evidence that accumulation of DNA damage following chronic adrenergic stimulation (for example, as a result of chronic stress) may be the result of synergistic eff ects of β-adrenergic stimulation on two molecular pathways -one directly leading to DNA damage, the other leading to a reduction in p53 levels [11].

The article
Using a mouse model, Hara and colleagues simulated chronic stress by prolonged pharmacological stimulation of β 2 -receptors with the β-adrenergic agonist iso proterenol, a synthetic analogue of adrenaline [11]. Th e investi gators fi rst demonstrated that chronic catecholamine stimulation leads to phosphorylation of histone H2AX, one of the earliest indicators of DNA damage.
Using a specifi c β 2 -antagonist, they then determined that the increased DNA damage occurred as a result of nuclear export and p53 degradation through receptorspecifi c mechanisms. Murine double minute 2 (MDM2) plays an important role in p53 nuclear export and degradation. In light of this fact, the authors were ableusing a com bination of receptor antagonists and phospho inositide 3-kinase and AKT inhibitors -to demonstrate that β 2 -adrenoreceptor activation resulted in MDM2 phos phory lation via the phosphoinositide 3-kinase/AKT cascade and accumulation of DNA damage in wild-type mouse embryonic fi broblasts. Th ey further found that arrestin beta 1 (ARRB1), which functions as an E3 ligase adaptor for MDM2 and p53, facilitated catecholamineinduced p53 degradation by MDM2. β-adrenergic stimulation of the phosphoinositide 3-kinase/AKT cascade can be stimulated by both the Gs-protein kinase A and the β-arrestin-mediated signaling pathways. Th rough the application of H-89, a protein kinase A inhibitor, and use of ARRB1-knockout or ARRB2-knockout mouse

Abstract
Accumulating evidence indicates that psychological stress can have deleterious infl uences on cancer development and progression, but the mechanisms responsible remain unclear. One possible mechanism is suggested by emerging evidence that DNA damage is increased by exposure to stress and stress hormones (for example, cortisol, catecholamines). Possible molecular mechanisms for such eff ects were the subject of a recent paper by Hara and colleagues, which suggests that chronic stress, through β-adrenergic stimulation, can induce two synergistic pathways that result in accumulation of DNA damage. Herein, we discuss the potential implications of these fi ndings for breast cancer etiology, progression, and treatment response. embryonic fi broblasts, the authors demonstrated that chronic catecholamine stimulation leads to accumulation of DNA damage by an ARRB1-dependent and p53dependent mechanism.
In summary, Hara and colleagues provided evidence that catecholamines can act through two pathways: via Gs-protein kinase A, and via ARRB1 inducing DNA damage [11]. Both pathways are activated as a result of stimulation of β 2 -adrenoreceptors, with the ARBB1 facilitating AKT-mediated activation of murine double minute, which in turn promotes MDM2 to bind and degrade p53, leading to the accumulation of DNA damage (Figure 1).

The viewpoint
DNA damage triggers a number of cellular responses, including repair mechanisms, cell-cycle checkpoint activity and apoptosis. Th e tumor suppressor protein that mediates many of these critical cellular functions (p53) is frequently mutated, and has been found to be inactivated or functionally downregulated in breast cancer. Th e upstream mechanisms that regulate p53 degradation and accumulation of DNA damage, which Hara and colleagues have described, could thus have signifi cant implications. Indeed, in precancerous 3T3 cells, stress hormones can cause induction of the DNA damage sensors Chk1 and Chk2, MDM2, and the protooncogene CDC25A, which is involved in cell-cycle delay following DNA damage, resulting in increased cell transformation [8]. Although the literature has come a long way towards recognizing the potential importance of psychological stress in the initiation and progression of breast cancer [12], few studies have explored the mechanisms through which stress hormones may impact breast cancer initia tion and progression. It is tempting to speculate that increases in stress hormones could promote DNA damage and inhibit countervailing processes, and thus lead to a predisposition to breast cancer.
Also, if stress hormones can induce DNA damage in breast cancer, could this damage contribute to diff erences in the effi cacy of chemotherapy drugs across individuals as a result of diff erences in their stress levels? Such personalized stress eff ects could have i mportant implications for cancer therapeutic strategies that are based on the induction of DNA damage in rapidly dividing cells. For example, in breast cancer cells treated with anthra cy clines -which work through intercalation of DNA and subsequent DNA damage -would heightened levels of catecholamines actually benefi t chemotherapy? Would stress-induced DNA damage impact drugs that work through other mechanisms, such as Taxol? Clearly, there is a need for further mechanistic studies to explore the eff ects of stress hormones on DNA damage pathways involved in breast cancer etiology and in response to chemotherapy treatment.  /AARB1/p53 P p53 U p p53