Crosstalk between Depression and Breast Cancer: History
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Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Zhen Ye
,
Kumar Ganesan
,
Mingquan Wu
,
Yu Hu
,
Yingqi She
,
Qianqian Tian
,
Qiaobo Ye
,
Jianping Chen

Breast cancer (BC) is a serious global challenge, and depression is one of the risk factors and comorbidities of BC. Recently, the research on the comorbidity of BC and depression has focused on the dysfunction of the hypothalamic–pituitary–adrenal axis and the persistent stimulation of the inflammatory response. However, the further mechanisms for comorbidity remain unclear. Epoxide metabolism has been shown to have a regulatory function in the comorbid mechanism with scattered reports. Hence, this article reviews the role of epoxide metabolism in depression and BC. The comprehensive review discloses the imbalance in epoxide metabolism and its downstream effect shared by BC and depression, including overexpression of inflammation, upregulation of toxic diols, and disturbed lipid metabolism. These downstream effects are mainly involved in the construction of the breast malignancy microenvironment through liver regulation. 

  • depression
  • epoxide metabolism
  • comorbidity
  • tumor microenvironment
  • breast cancer

1. Introduction

Cancer is one of the malignant diseases with the highest mortality in the world, and its incidence continues to grow rapidly [1,2]. The leading cause of cancer-related mortality among the female population is breast cancer (BC) [3]. Since 2020, BC has been the major cause of cancer incidence worldwide, accounting for 11.7% of all cancer cases [3,4]. BC is also the fifth highest cause of cancer deaths around the world [3]. In addition, BC is an obstacle to improving life expectancy in each country, causing a heavy economic burden and health and social challenges globally [3]. BC is a highly heterogeneous disease whose development is associated with genetic, dietary, and environmental factors [5]. Various types of BC can be broadly classified as hormone receptor status (estrogen receptor, ER, or progesterone receptor, PR), human epidermal growth factor receptor status (HER2), and triple-negative status (TNBC) [5, 6, 7, 8]. The current mainstream treatment options include conventional chemotherapy, monoclonal antibodies, and coupled systemic administration [5]. Although increased levels of diagnosis of BC over the years have led to increased survival rates, the side effects of treatment, the impact of stress, and the unsatisfactory quality of survival have still attracted public concern [9]. BC has a high rate of physical and mental comorbidity, mainly due to chronic stress [10]. Depression, as a vital risk factor and comorbidity of BC, has plagued women with BC for decades. In the absence of the precise management of individuals, families, and professional domains, female BC patients are placed under mental stress, which eventually brings a heavier physical burden. Studies have illustrated that depression is an independent predictor of higher frequency hospitalization, longer hospitalization, lower quality of life, and lower treatment compliance [11]. Depression has also been demonstrated to be an important predictor for the diagnosis of advanced BC patients, and the suicide rate of BC patients has highly correlated with clinical symptoms of depression phenotypes [12]. It was reported that comorbid depression is associated with poor prognosis and increased mortality in cancer patients [13]. A study demonstrated that the prevalence of depression in BC patients is 15% during and after medical cancer treatment. The treatment of anxiety and depression are associated with decreased neurocognitive function and reduced hippocampal volume following chemotherapy [9,14, 15, 16, 17]. What is more, in the context of the current global prevalence of infectious diseases, BC patients are prone to emotional disturbances and cognitive dysfunction due to the impact of work and employment [18]. A meta-analysis demonstrates that negative emotions significantly increase the risk for the incidence of BC [19]. Thus, the comorbidity of BC and depression is an inescapable biomedical problem.

Hitherto, most studies addressing the comorbidity of BC and depression have focused on four aspects: inflammation and oxidative/nitrosative stress, reduced immune monitoring, abnormal activation of the autonomic nervous system, and the hypothalamic–pituitary renal axis (HPA) [20]. In fact, the imbalance of peripheral dopamine (DA) and kynurenine (KYN) are proposed to positively predict depression in BC patients [21]. Moreover, the persistent activation of the HPA and sympathetic nervous system is believed to promote BC growth. Unfortunately, due to the dispersion of information, the bridging mechanism between depression and BC is still unclear since the etiology and final effect of the comorbidity have only been partly discussed. Epoxide metabolism is an important metabolic process that mediates inflammation, tumor, and immune surveillance, which mainly occurs in the liver, kidney, and blood vessels [22].

Epoxide metabolism is noted to play a significant regulatory role in BC. Soluble epoxide hydrolase (sEH) is an essential intermediate enzyme in epoxide metabolism and has a vital effect on the pathogenesis of depression and BC [22, 23]. Several studies have indicated that upregulation of sEH is closely related to neurological disorders [24]. A decrease in sEH level is also found in BC tissues, whereas an increase in sEH level inhibited BC proliferation. Other scholars have shown that sEH can promote BC cell proliferation by hydrolyzing toxic epoxides, which is inconsistent with previous studies [25, 26]. Therefore, sEH-mediated epoxide metabolism might be a crucial area for investigation and one of the critical comorbid mechanisms of BC and depression. However, the presented evidence is controversial. According to the study, epoxide metabolism mainly occurs in the liver, and sEH may have different effects on different subtypes of BC. Furthermore, epoxide metabolism is involved in mediating immune responses and regulating lipid homeostasis in the tumor microenvironment (TME) [27]. Researchers have demonstrated that the levels of plasma interleukin 6 (IL-6) in patients with BC and depression are higher and are also regulated by sEH [28,29]. The epoxide metabolism mediated by sEH might be related to a deeper mechanism, which is the key point of the controversy.

2.Depression Is an Important Risk Factor and Comorbidity of BC

Depression, one of the reported risk factors for cancer, is known as a comorbidity of BC. Researchers have found that BC survivors experience a high rate of depression, and the incidence of depression during and after treatment is 15% [9, 30]. Current research has underlined the neurohormonal signaling system as the major shared mechanism of BC and depression. The sympathetic nervous system (SNS) and HPA are two stress responses that affect the nervous system and contribute to BC development [31]. When depression occurs, chronic stressors activate the HPA axis, resulting in adrenaline and catecholamines release. Following the HPA axis activation, adrenaline activates BC-adrenergic receptors, accumulates myeloid-derived suppressor cells (MDSCs), and promotes BC development [32]. Cortisol secreted by the adrenal cortex promotes BC cell development by activating the glucocorticoid receptor (GR) signaling pathway, serum/glucocorticoid-regulated kinase 1 (SGK1), and mitogen-activated protein kinase phosphatase 1 (MKP1)/dual-specific phosphatase 1 (DUSP1) [33]. At the same time, cortisol leads to a reduction in tumor immunosurveillance by suppressing immune function with decreased natural killer (NK) cell activity and T cell proliferation [34] (Figure 1).

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Figure 1. The HPA axis activated by stress is reported to promote cortisol, adrenaline, and catecholamine release. Cortisol could inhibit the activity of NK cells and T cells, as well as promote the activation of GR, MKP1, SGK1, and DUSP1, which are the positive factors for breast cancer progression. Catecholamine also plays a promoting role for BC. Moreover, adrenaline could upregulate the bioactivity of MDSCs, which indirectly promote the progression of BC. 

Further, depression is associated with BC partly due to the increase in macrophage activity induced by depressive phenotypes. The M1 macrophages are an important factor in inflammation in patients with severe neurological disorders [35]. Research on major depressive disorder found elevated levels of circulating cytokines in peripheral blood mononuclear cells (PBMCs), as well as increased levels of NF-kB in PBMCs [36]. Adipocytes and BC tumor cells release chemokines (e.g., C-C motif chemokine ligand 2 (CCL2), C-C motif chemokine ligand 5 (CCL-5), or colony-stimulating factor (CSF-1)) to promote the migration of monocytes and macrophages into the BC microenvironment [37,38]. These macrophages contain M1 and M2 phenotypes, while the M1 macrophages are always transformed into M2 within the BC microenvironment, and so are the monocytes [39, 40, 41, 42]. Adipocytes in the breast stroma are an important source of interleukin 10 (IL-10), which also contributes to the polarization of macrophages to the M2 phenotype in BC [43, 44, 45]. Clinical studies have also indicated that IL-10 is an independent factor in poor prognosis in TNBC, ER-negative, or PR-negative cases [46,47].

Chronic systemic inflammation induced by prolonged stress in depression has clearly been shown to be an initiating factor in carcinogenesis [48]. IL-6, one of the proinflammatory cytokines, is a signaling promoter and pathological product of depression [49]. Studies have shown that high levels of IL-6 are related to the chronic course of depression, and the severity of depression in patients with high expression of IL-6 is increased as well. The research results of elderly patients with depression show higher levels of IL-6 than in healthy elderly people [50]. Likewise, IL-6 also plays an instrumental procancer role in BC. Clinical evidence indicates that IL-6 induction is associated with a poor prognosis for a patient with BC, with plasma IL-6 levels showing a positive correlation with pathological grade. A preclinical study derived that the IL-6/ IL-6R/ gp130 pathway promotes the growth and metastasis of BC, while inhibiting the pathway is not conducive to the development of BC. Therefore, IL-6 may contribute to BC and depression in comorbid states. Additionally, TNF-α is a pathogenic cytokine in depression. One study found that the levels of proinflammatory cytokines TNF-α and IL-6 in patients with major depression increased significantly [51]. Meanwhile, anti-TNF-α drugs are found to be antidepressants [52]. The dual effect of TNF-α on BC is discussed as well [53]. The immune response further suggests that chronic inflammation is an important basis for depression and BC comorbidity. The fact of the hormone regulation and cytokine effect have been widely mentioned, but the intermediate stage of the pathogenesis of the comorbidity is still unclear.

3. Different Status of sEH Mediates Epoxide Metabolism in BC

sEH-mediated epoxide metabolism not only operates in depression but also in the formation of the BC microenvironment. However, the effect of sEH on BC is controversial. On the one hand, the sEH causes the decrease in EETs, a promoting factor on BC[54]. Meanwhile, 14, 15-EET can promote angiogenesis in BC tissues and upregulate vascular endothelial growth factor (VEGF)[55]. A clinical study revealed that 14, 15-EET induced integrin αvβ3 expression and FAK/PI3K/AKT activation, which strengthen stromal production and cisplatin resistance in BC cells (MCF-7 and MDA-MB-231) in vivo[56].
On the other hand, a cytotoxic leukocyte metabolite can be degraded to diol by sEH, indicating that diols can stimulate the proliferation of MCF-7 cells (ER+PR+HER2-) [24，57，58，59]. More seriously, inflammatory breast cancer (IBC) is considered to be a rapidly developing and metastasizing type of BC. The degradation of EETs leads to the generation of a proinflammatory microenvironment, which in turn becomes a risk factor for IBC. Hence, it appears that sEH has a further promotional influence on BC. Researchers have found that BCs with different receptor phenotypes have different levels of sEH, implying that epoxide metabolism involved in sEH will have different effects on different subtypes of BC, or even maybe the opposite [7，25]. Several pieces of evidence for the sEH influence on different phenotypes of BC have been identified via omics-based pathway analyses [7]. The study demonstrated that sEH expression is highly positive in HER2+ (75%), ER+PR+ (68%), and triple-positive BC (TPBC) (67%), but the weakest expression appeared in TNBC (46%). Meanwhile, the sEH inhibitory effects are significantly lower in HER2+ (33% strongly positive for sEH) BC, especially compared with TNBC. TNBC maintains the lowest sEH expression, while CYP450, including CYP2C8, 2C9, 2J2, and CYP3A4, exhibits strong expression in TNBC, which is known to promote the conversion of AA, LA, DHA, and EPA into EETs, EpOMEs, EpETEs, and EpDPAs. The EETs derived from these CYP450 have been confirmed to promote invasion and metastasis in TNBC [54]. Even though TNBC causes sensitive reactions to CYP450 and EETs, a different subtype of TNBC still shows the opposite phenomenon[7]. TNBC has been reported to be divided into several subtypes, including the mesenchymal-like subtype and basal-like subtype[60，61，62，63]. Depletion of endogenous CYP450 attenuates the metastatic phenotype of mesenchymal-like TNBC cells[7]. Conversely, CYP2C19 depletion or any compound inhibitor treatment has no significant effect on the migratory and invasive potential of basal-like TNBC cells, and the inhibition of sEH failed to induce significant changes in total EET levels in any of the basal-like TNBC cell lines[7].  The metastatic and invasive capacity of basal-like TNBC is independent of CYP450. CYP450-mediated EET metabolisms have a stronger correlation with mesenchymal-like TNBC. 
The expression or activity of targeted CYP450 has a more effective influence in reducing the metastatic burden of the mesenchymal-like TNBC subtype [7]. Meanwhile, HER2+ BC is found unaffected by either of the EETs. On the contrary, another study attributed the tamoxifen resistance in MDA-MB-361 (ER−/PR−/HER2+) to overexpression of CYP3A4, partly by enhancing 11,12-EET biosynthesis [64], while it is mentioned in the study by Maria Karmella Apaya that MCF-7 could not be affected by any EET [7]. Contradictory evidence reveals the existence of deeper complicated network mechanisms. Of note, sEH maintains a higher expression in hormone receptor-positive BC with the possible production of leukotoxins, further suggesting that sEH may be a key factor in the comorbidity of depression and hormone receptor-positive BC. sEH might promote the growth of BC by degrading epoxides and generating specific toxic diols, particularly in hormone receptor-positive BC.

4. Depression-Associated sEH Promotes Liver Dysfunction and Breast Cancer

As mentioned above, with the increase in depression exploration, extracerebral pathological alterations have been paid more and more attention. As the main organ of lipid metabolism, especially the metabolism of epoxide, the liver has been proposed to have an unexpected connection with brain functions [65,66,67,68,69]. The pathogenesis of Alzheimer’s disease (AD) is believed to be closely related to depression [70,71]. In particular, major depression and AD share biological processes and pathways, including 77 disease-related genes and 102 pathways [72]. Amyloid β (Aβ) is one of the vital shared pathogenic targets [73,74,75,76]. AD has been pointed out to be significantly associated with liver dysfunction [77]. The liver and kidney are the main extracerebral organs for the clearance of circulating Aβ [77]. Low-density lipoprotein receptor 1 (LRP-1), which is mediated through the liver, has been shown to regulate multiple tight junction proteins in the blood–brain barrier endothelium [78]. Studies also showed that those central mechanisms are involved in the neurological and endocrine systems of the brain leading to neuroendocrine regulation of CYP450 gene expression. Such mechanisms have been shown to involve the dopaminergic, noradrenergic, and 5-hydroxytryptaminergic systems of the brain with hypothalamic endocrine centers, among which repetitive restraint stress (RS) increases hepatic CYP2D1/2 activity in a stress-specific manner, while the main effectors of the stress system, glucocorticoids and epinephrine, are highly induced by CYP3A1/2 [79,80,81,82,83,84]. Epinephrine also induces the expression of CYP2C11 and CYP2D1/2. Studies have shown that human hepatocyte microsomes are the primary site of systemic CYP450, sEH-mediated epoxide metabolism [85]. This discovery further supports the importance of hepatocyte epoxide metabolism in depression–BC comorbidity.
Researchers also disclosed that psychiatric disorders induce liver dysfunction [77]. A study found that sEH in the livers of chronically stressed experimental animals increased specifically without its appearance in other organs and caused nonspecific changes in LOX and COX signaling pathways [86]. Furthermore, the specific knockdown of the hepatic sEH gene Ephx2 suppressed the expression of the depression-like phenotype. Moreover, the important hydrolase is predominantly expressed in hepatocytes [86]. The evidence suggests that hepatic sEH is one of the main causative factors of psychiatric disorders including depression. Additionally, sEH has been raised as the critical molecule in the brain–liver axis, with a positive correlation between sEH protein in the parietal cortex and sEH protein in the liver [87]. Thus, the downstream effects of hepatic epoxide metabolism, including inflammation, liver dysfunction, and lipid metabolisms, may be components of contributors to BC.
The effects of depression on the liver are known to be reflected in inflammation, oxidative damage, and reduced immune surveillance [65,69,88]. From the perspective of molecular mechanisms, the upregulation of hepatic sEH is one of the pivotal upstream causes of liver damage, liver fibrosis, and hepatitis [65,89,90,91]. The inhibition of hepatic sEH significantly reduces endoplasmic reticulum stress in hepatocytes and maintains low expression of prostaglandins and triglycerides, thereby reducing high-fat-diet-induced inflammation [92]. A notable observation is that overexpression of hepatic sEH increases liver triglyceride levels and hepatic inflammatory response [65,69].
Surprisingly, the induced expression of sEH in the liver only occurred in a long-term rather than short-term high-fat diet. Furthermore, sEH inhibition attenuates the high-fat-diet-induced plasma levels of proinflammatory cytokine increase and the adipocytic cytokine mRNA upregulation. It is thus clear that depression promotes specific upregulation of hepatic sEH, which is a potential inflammatory injury factor in the liver [92,93]. What is more, overexpression of sEH in the liver directly affects the balance of epoxide metabolism. The pathological changes in the liver are crucial to the disruption of the internal environmental homeostasis, which provides a potentially favorable environment for the development of BC.
Another noteworthy point is that ω-6 PUFAs and ω-3 PUFAs, as the precursors of DHA, EPA, AA, and LA, are clearly involved in the pathogenesis of depression [94]. Studies have shown that ω-3 PUFAs exert anti-inflammatory effects in the brain by regulating microglia function to maintain homeostasis, which improve fatty acids for the pathogen. At the same time, ω-6 PUFAs have been considered as promoting factors of inflammation, while the ability of dietary LA to increase the levels of inflammatory markers is influenced to some degree by the level of adiposity [94,95]. The ratio of ω-6 PUFAs/ω-3 PUFAs is considered to affect the balance of lipid metabolism [95,96]. A Mediterranean diet with high ω-3 PUFA levels has been mentioned to alleviate depressive symptoms and even decrease the prevalence of malignancies such as breast, lung, prostate, and colorectal cancers [97,98]. In addition, ω-3 PUFAs have been found to attenuate microglia-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway [99].
It has also been shown that an unhealthy diet can lead to obesity, which is highly correlated with a chronic inflammatory environment and depression. A high ratio of ω-6 PUFAs/ω-3 PUFAs has been demonstrated to be an unhealthy dietary pattern [100,101]. Western diets, another popular diet construction, show a high ω-6 PUFAs/ω-3 PUFAs ratio of 15/1 to 16.7/1 [100,102]. Western diets have been shown to induce hyperthrombotic and proinflammatory states [101,103,104,105,106]. ω-6 PUFAs and ω-3 PUFAs can be converted into EPA, DHA, AA, and LA after ingestion, which can be further converted into EETs, EpOMEs, EpETEs, and EpDPAs. This shift suggests that the Western diet promotes an imbalance in lipid metabolism, which leads to a range of proinflammatory and carcinogenic effects [22,23,107]. In addition, the dietary structure of high ω-6 PUFAs/ω-3 PUFAs is conducive to the growth and development of BC. Studies have discovered that LA is the most abundant polyunsaturated fatty acid in the Western diet [95,96], where the consumption of butter, corn oil, the rice plant (Oryza Sativa L.), and soybeans leads to significantly increased hepatic LA consumption and promotes LA metabolism via CYP450 (mainly by CYP2J2, CYP2C8, and CYP2C9) to produce 9, 10-EpOME (leukotoxin) and 12, 13-EpOME (isoleukotoxin) [108,109,110,111,112,113]. Another important fact is that stress is reported to induce the hepatic PXR expression, which is followed by induced hepatic CYP3A and CYP2C expression [81]. Therefore, the response of high dietary ω-6 PUFAs to depression results in high sEH expression promoting the production of 9, 10-DiHOME (leukotoxin diol) and 12, 13-DiHOME (isoleukotoxin diol) [55,82]. In addition, a high ω-6 PUFAs/ω-3 PUFAs diet may increase breast cancer risk [114,115,116,117]. Moreover, it has been shown that LA promotes the proliferation of MDA-MB-231 breast cancer cells by activating the EGFR/PI3K/Akt signaling pathway [118,119]. Meanwhile, AA has been found to have a similar effect as well [119]. It is worth noting that excessive LA intake has been implicated in the development of obesity and liver dysfunction [120,121,122,123,124,125,126]. This effect is fatal to BC patients, especially BC with obesity. Basically, hepatic sEH-mediated epoxide metabolism is an important mechanism by which the liver regulates the comorbidity of depression and BC.
Under the stimulation of chronic depression, chronic stress leads to the continuous increase in inflammatory cytokines leading to chronic persistent inflammation. Although the hypothalamic–adrenal axis is one of the important regulatory pathways of chronic inflammation induced by chronic stress, sEH-mediated epoxide metabolism is also an important regulatory pathway [83]. This is because EETs degraded by sEH are also important contributors to the creation of a proinflammatory endotrophic environment. Fatty liver has been identified as consistent with increased neuro-proinflammatory cytokines and amyloid β deposition in the brain of mice induced by a high-fat diet [127]. Thus, abnormal lipid metabolism and hepatic inflammation mediated by disturbances in hepatic epoxide metabolism are directly related to neuroinflammation and pathological alterations in amyloid β in the brain. Importantly, sEH upregulation increases EET degradation and promotes cytokine expression. A study illustrated that dual inhibitors of sEH and COX-2 improved hepatic fibrosis and portal hypertension and downregulated IL-6 levels, suggesting that IL-6 plays a driving role in hepatitis [128]. The prevalence of nonalcoholic fatty liver diseases (NAFLD) in patients with breast cancer is significantly higher than in healthy controls, while hepatic sEH is a key enzyme for NAFLD [129]. Moreover, breast cancer patients with NAFLD showed poorer prognosis in terms of recurrence [129,130].
In addition, as mentioned earlier, depression-mediated neuroinflammation is associated with IL-6, and there is also a positive relationship between this interleukin and the construction of TME in BC [131]. Therefore, IL-6-related pathways may be one of the downstream pathological developmental pathways of epoxide metabolic disorders. Currently, several studies are aimed at blocking the IL-6 receptor and its downstream signaling molecules to develop BC-related therapeutic regimens [29,132]. Generally, systematic chronic inflammation is a beneficial environment for BC development, which is tightly connected with adipose issues (especially cancer-associated adipocytes) [132,133,134,135,136]. This review points out that another potential target, blocking hepatic sEH rather than breast tissue sEH, might be a suppressor in partially comorbid BC and depression populations.

References

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This entry is adapted from the peer-reviewed paper 10.3390/molecules27217269

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