Breast cancer and social environment: getting by with a little help from our friends

Stress-related pathways linked to breast cancer progression and their susceptibility to social modulation

All living creatures experience stress; in the short term, increased activation of the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis is typically an adaptive response to a stressor. However, as activation of these two systems becomes chronic and grows resistant to regulation, the response becomes maladaptive, increasing the individual’s susceptibility to a wide range of diseases [11]. Social isolation is a particularly potent chronic stressor for social species, and perceived isolation (loneliness) has been demonstrated in humans to correspond with increased circulating stress-related hormones [26]. Although a direct link between social environment and dysregulation of the SNS and HPA axis has not been established in patients with BC, impaired regulation of either of these endocrine systems is predictive of reduced BC-related survival [27, 28]. The primary effectors of the SNS and HPA axis are catecholamines and glucocorticoids (GCs), respectively, and these hormones are capable of modulating tumor progression. Thus, it is possible that increases in glucocorticoids and adrenergic hormones elicited via social isolation could modify breast tumor development (Fig. 2).

Proposed mechanisms through which social isolation influences breast cancer outcomes in women. Socially isolated individuals tend to exhibit increased activation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS). Among patients with breast cancer (BC), increased cortisol is associated with reduced natural killer cell (NKC) count and cytotoxicity, and increased risk of early mortality. There is also the supposition that increased concentrations of endogenous catecholamines (adrenaline and noradrenaline) promote tumor development, metastasis, and tumor progression because the use of ?_1/?₂ receptor antagonists for other health conditions is associated with less aggressive tumors and reduced early mortality among patients with BC

Converging evidence from several studies indicates that sympathetic nervous system (SNS) activation can facilitate BC progression. The SNS primarily exerts its effects through the production of adrenaline (epinephrine) from the adrenal medulla and noradrenaline (norepinephrine) from post-ganglionic neurons. In the context of cancer, most of the research to date has focused on signaling via beta-1 (?₁) and beta-2 (?₂) adrenergic receptors. Retrospective studies indicate that the use of ?_1/?₂ antagonists (beta blockers) is associated with the presentation of less advanced BC, reduced metastasis, increased relapse-free survival, and reduced BC-related mortality [29–31]. A phase II clinical trial has been initiated to empirically test whether propranolol (?_1/?₂ antagonist) co-administration increases the efficacy of chemotherapy in patients with BC (NLM Identifier NCT01847001). There are several direct and indirect mechanisms through which ?-adrenergic signaling may be influencing BC development, including tumor cell invasion [32], angiogenesis [33], tumor cell survival [29], and tumor-immune interactions [34]. Correspondingly, treatment with ?-adrenergic antagonists prevents the negative effects of catecholamines on cancer growth and progression in several rodent cancer models [32, 35–37]. In addition, social isolation increases noradrenaline concentration within human ovarian tumors [38]. Together, these studies provide strong support to the hypothesis that SNS activation plays a critical role in BC progression, while offering a potential mechanism through which social isolation could be influencing BC development.

Glucocorticoids also may directly and indirectly influence tumor growth through their involvement in the fundamental biological processes of metabolism, immune function, angiogenesis, circadian rhythmicity and neuronal function. Indeed, among patients with metastatic BC, a blunted diurnal cortisol rhythm (i.e., the primary glucocorticoid in humans) is associated with reduced survival duration and the suppression of natural killer cell (NKC) counts [28]. NKCs have an innate ability to target and kill cancer cells, and higher NKC activity has been shown in patients with BC to predict disease-free survival [39] and are associated with increases in perceived levels of social support [40]. In culture, glucocorticoids promote tumor cell proliferation [41] and cancer cell survival [42]. In mice, glucocorticoids released by chronic restraint stress promote tumorigenesis through regulation of the tumor suppressor p53 [43]. Excess chronic glucocorticoids also may interfere with the efficacy of chemotherapy; both chronic stress and supplementation with exogenous glucocorticoids produce resistance to paclitaxel, in turn leading to larger tumors [44, 45]. Likewise, treatment with a glucocorticoid receptor antagonist increases the efficacy of paclitaxel-induced cytotoxicity and apoptosis in glucocorticoid-receptor-positive, triple-negative, BC cell cultures [46]. Glucocorticoids also are immunomodulators capable of altering host-tumor interaction; indeed, several immune cells that are demonstrated to play an important role in tumor development, including B cells, T cells, NKCs, and macrophages, can be modified through glucocorticoid signaling (reviewed in [47]). The effects of perceived isolation on immune function and inflammation via glucocorticoid signaling are extensive. Genome-wide expression analysis has revealed that adults with increased loneliness have upregulated expression of pro-inflammatory transcripts (associated with nuclear factor kappa B activation) and downregulated anti-inflammatory (associated with glucocorticoid receptor activation) gene expression [48]. In addition, loneliness may directly reduce the sensitivity of the glucocorticoid receptor, leading to decreased anti-inflammatory effects of glucocorticoids in isolated individuals. Loneliness is indeed associated with changes in circulating neutrophil-lymphocyte and neutrophil-monocyte ratios, both surrogate measures indicating systemic leukocyte glucocorticoid resistance in lonely individuals [49].

Interestingly, however, chronic synthetic glucocorticoid use for other health reasons was not associated with increased risk of BC or its recurrence in a large cohort of Scandinavian women [50, 51]. Furthermore, synthetic glucocorticoids (e.g., dexamethasone) are routinely used to combat the acute hypersensitivity and emetic side-effects of chemotherapy, in turn greatly improving tolerability for some patients. Whether the prophylactic use of glucocorticoids in this regard reduces the efficacy of the chemotherapy in patients, as suggested by the rodent and cell culture studies described above, is not known. To our knowledge, a systematic study of prophylactic glucocorticoid use in patients undergoing chemotherapy has not been conducted, although a clinical study examining the effects of various chemotherapy dosing regimens on disease-free and overall survival in 1572 breast cancer patients reported that dexamethasone use did not affect outcome [52]. This potential discrepancy between the effects of chronic exposure to excess endogenous versus synthetic glucocorticoids, and the direct effects of glucocorticoids on the tumor cells versus the whole body response is critical to resolve in order to optimize treatment for patients with BC. At any rate, HPA axis dysregulation of endogenous glucocorticoids provides another plausible physiological link between social isolation and BC; social isolation alters cortisol rhythms among otherwise healthy individuals [53], while disruption of diurnal cortisol rhythms is associated with a poorer prognosis among patients with BC [28].