Dysregulation of GABAergic system well known to be involved in SCZ pathogenesis is also linked to carcinogenesis. For instance, while epigenetic down-regulation of GAD1 is shown in SCZ patients (Bharadwaj et al. 2013), over-expression of GAD1 is observed in oral squamous cell carcinoma and it has been associated with a higher degree of invasion and migration of cancer cells (Kimura et al. 2013). In breast cancer, the metastatic cells entering into the brain exhibit GABAergic phenotype (higher levels of GABA-A receptors and RELN) in order to co-opt to the brain microenvironment (Neman et al. 2014). Notably, the expression of GABA-A receptor subunits is also increased in human liver cancer, and GABA could inhibit cell migration and invasion mediated by GABA-A receptors (Chen et al. 2012c). Considering that GABAB ligands also directly interact with the CXCR4 receptors (Guyon et al. 2013), the drugs known to modulate GABAergic system may be of use for treating specific cancers with higher levels of CXCR4 expression (Fig. 5.1).

The higher expression of GAD1 in benign and malignant prostatic tissue led to the conclusion that; GAD1 may be a prostate-specific tissue biomarker. However, GAD1 expression decreases as the Gleason score increases in prostate cancer (Jaraj et al. 2011) suggesting that in addition to RELN, the reduced risk of prostate cancer in SCZ patients may also be due to epigenetic down-regulation of GAD1 in these patients. These observations lend additional support for therapeutic utility of GABAergic drugs as well as epigenetic modifiers in specific types of cancers.

Catechol-O-methyltransferase (COMT) plays a major role in the metabolism of dopamine as well as the carcinogenic catechol estrogen. A recent meta-analysis concluded that the Val/Val polymorphism of COMT, the overactive genotype, is linked to a higher risk for endometrial cancer during the post-menopausal period in women (Lin et al. 2013b). However such an association was not found in an earlier meta-analysis (Qin et al. 2012), another meta-analysis confirmed that the Val158Met polymorphism of COMT is involved in breast cancer risk in Caucasians (He et al. 2012). An association with the Met/Met (AA) genotype for breast cancer risk has been confirmed by a different meta-analysis in Chinese population (Tian et al. 2014). The reduced activity of membrane-bound catechol-O-methyltransferase (MB-COMT) due to promoter DNA hypermethylation has also been observed in endometrial cancer cell lines as well as in endometrial cancer tissues (Table 5.1) (Sasaki et al. 2003).

We examined DNA methylation and the corresponding expression of MB-COMT in post-mortem brains as well as saliva samples from the SCZ and BD patients versus control subjects (Abdolmaleky et al. 2006; Nohesara et al. 2011). In contrast to cancer, the MB-COMT promoter DNA was significantly hypomethylated, and MB-COMT gene expression was significantly increased in SCZ and BD patients, compared to the control subjects (Abdolmaleky et al. 2006). Interestingly, while the rate of pancreatic cancer is higher in SCZ patients, an increased expression of COMT was also observed in pancreatic cancer cell lines as well as pancreatic ductal adenocarcinoma compared to the normal pancreatic tissues (Wu et al. 2012).

Notably, beside COMT, monoamine oxidase A (MAOA), another gene encoding an enzyme involved in the degradation of dopamine as well as serotonin was found to exhibit increased expression in advanced prostate cancer (Flamand et al. 2010). However, its expression is epigenetically silenced in cholangiocarcinoma due to promoter DNA hypermethylation (Huang et al. 2012). Hypermethylation of specific CpG sites of MAOA was also reported in male SCZ patients (Chen et al. 2012a). These findings, although diverse, support that epigenetic modifications of genes related to dopaminergic system might serve as targets for cancer therapy. This idea gains additional support from the observations that the inhibitory effects of Epigallocatechin 3-O-gallate (EGCG) on the growth of lung cancer cell lines is synergistically potentiated by COMT inhibitor drugs such as entacapone and tolcapone (Forester and Lambert 2014) and MAOA inhibitors exhibit antioncogenic effects in advanced prostate cancer (Zhao et al. 2009; Flamand et al. 2010).

Adiponectin is a protein hormone exclusively secreted from the adipose tissues and in contrast to SCZ, is found at reduced level in plasma of patients with several types of cancers as well as obesity linked to insulin resistance and type 2 diabetes (Kishida et al. 2014; Hebbard and Ranscht 2014). The use of adiponectin receptor agonists such as AdipoRon, which is an orally active small molecule and act on both AdipoR1 and AdipoR2 receptors, to activate AMPK and PPAR-α pathways, respectively, has been proposed for the treatment of obesity-related disorders such as type 2 diabetes and cancer (Okada-Iwabu et al. 2013). In fact, in a study that used human and mouse colon cancer cell lines, both adiponectin and metformin additively reduced the malignant potential of colon cancer. The major mechanism proposed for this effect is that; adiponectin and metformin inhibit the IL-1β signaling and decrease malignant potential through their effects on the expression of p53 (a tumor suppressor), p21, p27, and cyclin E2 (genes regulating cell cycle) involving AMPK/LKB1 pathways (Moon and Mantzoros 2013).

As mentioned above, in the first five years of SCZ diagnosis and before the use of antipsychotics, the rate of cancer is lower in SCZ compared to the general population. However, because of the poor nutritional state of SCZ patients and more importantly the use of atypical antipsychotic drugs with common side effects such as weight gain and metabolic imbalance, the innate lower risk of cancer is found to decline in this group of patients (Ji et al. 2013; Chen et al. 2013; Manzanares et al. 2014). It is important to note that, in SCZ patients, treatment with atypical antipsychotic drugs decreases the circulating adiponectin at levels comparable to patients with diabetes. Adiponectin is reported to exhibit anti-angiogenic and tumor growth-limiting properties during in vitro studies and its level is inversely correlated with several malignancies that occur later in life (Adachi et al. 2012; Tsai et al. 2011; Song et al. 2013a, b; Dalamaga et al. 2012). While the circulating levels of adiponectin with insulin-sensitizing, anti-inflammatory, proapoptotic, anti-proliferative properties and cancer protectiveness declines with the use of atypical antipsychotics in SCZ (and bipolar disorder patients), current data, considering the higher levels of TGF-β in SCZ patients indicates that; metformin may not only be useful in the treatment of metabolic syndrome and the increased cancer risk, but also psychotic symptoms of SCZ patients as an inhibitor of TGF-β signaling pathway. In fact, excess weight gain and/or obesity not only is an emerging worldwide heath problem in general population, it is also an important issue in psychiatric patients, especially in SCZ patients under atypical antipsychotic drug treatment which have well known weight gain as the side effect (Subramaniam et al. 2014). Excess body weight is also considered as a risk factor for postmenopausal breast cancer, endometrial and ovarian cancer, pancreatic cancer, renal cell cancer, esophageal adenocarcinoma, hematological malignancies, high-grade prostate cancer, colon, thyroid, and gallbladder cancers (Dalamaga et al. 2012). There is a tendency for a higher frequency of a number of these cancers in SCZ patients using antipsychotic drugs.

VEGF is a growth factor implicated in cancer progression and metastasis. A decreased level of VEGF mRNA has been reported in the dorsolateral prefrontal cortex of SCZ patients (Fulzele and Pillai 2009). Furthermore, a low level of serum VEGF in Alzheimer’s disease (Mateo et al. 2007), and a significant increase in the VEGF serum level following the clinical improvement of drug resistant depressed patients treated by electroconvulsive therapy (ECT) support an important role for VEGF in neuropsychiatric disorders (Minelli et al. 2011). In an animal study, VEGF was found to mediate the anti-depressive effects of cAMP down-stream events in the adult hippocampus during the treatment by antidepressants (Lee et al. 2009). Chronic treatment with lithium could also attenuate the stress-induced decrease of VEGF expression in the hippocampus in stressed animals, thus the therapeutic efficacy of lithium as a mood stabilizer may be mediated by VEGF (Silva et al. 2007; Guo et al. 2009). VEGF is considered as a neurotrophic factor and has been implicated in neuronal survival, neuroprotection, regeneration, growth and differentiation (Rosenstein et al. 2010). As reported in a mouse model of diabetes, inhibition of the VEGF receptor 2 (VEGFR2) mediated signaling results in endothelial dysfunction and vascular problems, which could be potentially reversed with the use of antioxidants (Warren et al. 2014). It is noteworthy that VEGF is inhibited by miR-126 which its dysfunction is strongly associated with angiogenesis and is especially expressed in endothelial cells, and down-regulated under hypoxic condition as shown in both in vitro and in vivo studies (Ye et al. 2014). There is also supporting evidence that mir-126 is a tumor suppressor, and the reduced level of miR-126 is a significant predictor of poor survival in many cancers (Yang et al. 2013a; Yu et al. 2013; Sun et al. 2013). Mir-126 also suppresses DNMT1 (Zhao et al. 2011) as well as CXCR4 expression (Fig. 5.1), and its tumor suppressing potential is mediated by the AKT and ERK1/2 signaling pathways (Liu et al. 2014). Interestingly, along with the decreased level of VEGF, the expression level of mir-126 is up-regulated in the postmortem dorsolateral prefrontal cortex of the brain in SCZ patients (Beveridge and Cairns 2012). This signifies that multiple aspects of epigenetic alterations are inversely regulated in SCZ patients versus cancer and provide additional support for the idea that; the identification of disease pathogenesis in either illnesses could help the design of novel therapeutics for both of these diseases.

FOXO genes, the O subclass of the forkhead family of transcription factors, mediate the effects of insulin and growth factors and are involved in cell metabolism, proliferation and apoptosis. The FOXO family members in humans are FOXO1, FOXO3, FOXO4 and FOXO6. The shared nature of FOXO protein family members (with the exception of FOXO6, which is exclusively nuclear) is translocated out of the nucleus upon phosphorylation by Akt/PKB proteins of the PI3K signaling pathway (Brunet et al. 1999). The loss of FOXO functions, has been detected in several types of human cancers and diabetes, a known risk factor for cancer (Monsalve and Olmos 2011; Eijkelenboom and Burgering 2013). FOXO3 is widely distributed in the adult brain and exhibits an increased expression during the brain development (Barthel et al. 2005). Activation of PI3K and Akt lead to the phosphorylation of FOXO and translocation from the nucleus to the cytosol, to prevent its DNA binding and transcriptional activity (Fig. 5.1). However, dephosphorylated FOXO can return to the nucleus and induce expression of genes that are involved in cell cycle arrest, apoptosis and resistance to oxidative stress. Human FOXO3 (FOXO3A) has been associated with longevity and some of the FOXO3 genetic variations are also linked to cancer, cardiovascular disease and deficit in cognitive functions (Rodriguez et al. 2013; Jia et al. 2014; Pan et al. 2014; Carbajo-Pescador et al. 2014; Di Bona et al. 2013). Epigenetic modifications of FOXO3 such as methylation of the lysine 270 of histone protein can also inhibit DNA binding of FOXO3 and prevent the neuronal cell death induced by oxidative stress (Xie et al. 2012). The decreased expression of the FOXO3 is associated with poor prognosis of human breast cancer and primary gastric adenocarcinoma (Jiang et al. 2013; Yang et al. 2013b). Interestingly, in C. elegans all antipsychotic drugs activate AKT pathway and inhibit nuclear localization of DAF16, the homologous gene of the human FOXO3 (Weeks et al. 2010) suggesting this mechanism as one of the underlying causes of the increased breast cancer risk in medicated SCZ patients.

The phosphorylation of FOXO3 is also increased by brain derived neurotrophic factor (BDNF) that inhibits its transcriptional activity in differentiated human SH-SY5Y neuroblastoma cells. Treatment with lithium in mood disorders alongside the decrease in the levels of FOXO3, inhibits its transcriptional activity and alleviates the proposed BDNF deficiency in mood disorders based on an in vivo study (Mao et al. 2007). In other in vivo studies, an increased serotonergic activity was found to result in phosphorylation of FOXO1 and FOXO3 in several brain regions, and reduce the nuclear distribution of FOXO1 and FOXO3. Similarly, chronic treatment with imipramine, an antidepressant drug with serotonergic and noradrenergic properties, could also increase FOXO1 and FOXO3 phosphorylation in brain (Fig. 5.1). Additionally, metformin also increases FOXO3 phosphorylation leading to a decreased FOXO3 nuclear localization (Takayama et al. 2014). Of note, the selective deletion of FOXO1 from the brain reduces anxiety level, and the FOXO3a-deficient mice exhibit antidepressant-exposed behavior (Polter et al. 2009). In humans, while the loss of FOXO function, has been linked to cancer (Monsalve and Olmos 2011), we found a highly significant increase in the expression of FOXO3 during gene expression profiling of the post- mortem brains of SCZ and to lesser extent in BD patients (Abdolmaleky and Thiagalingam, manuscript in preparation). Therefore, similar to other genes/pathways mentioned above FOXO also has opposite roles in cancer versus SCZ as well as BD proposing the indication/contraindication of specific psychiatric drugs in cancer therapy and vice versa.

Similar to SCZ, a decreased rate of cancer has been reported in patients with Huntington’s disease (HD) in different countries (Sørensen and Fenger 1992; Ji et al. 2012). Interestingly, a large fraction of patients with HD exhibit SCZ-like symptoms before or after the appearance of HD symptoms. An increased CAG repeat expansion in the exon 1 of gene coding an expanded chain of glutamines in huntingtin (Htt) protein is responsible for HD as an inherited neurodegenerative disorder. Although the underlying mechanisms of the reduced cancer risk in patients with HD have not been fully explored, it has been attributed to an increased apoptotic capacity of the expanded polyglutamine repeat in an animal study using p53 deficient mice (Ryan and Scrable 2008).

The striatal neurons expressing dopamine receptors predominantly become degenerated in HD patients, and the degree of striatal neuronal loss is inversely linked to the age of death in HD patients. Thus the mutated Htt, which is predicted to exhibit prominent toxic activity in this brain region (Hadzi et al. 2012), may also be involved in the senescence of other cells. Interestingly, low doses of a selective dopamine type 1 (D1) receptor agonist such as 100 μM of dopamine which activate adenylate cyclase, accelerates the formation of mutant Htt nuclear aggregates and increases the rate of cell death in neuroblastoma cell lines (Robinson et al. 2008). Earlier studies also showed an accelerated formation of aggregates and cell death with 1 mM of dopamine in striatal primary cultures containing human HTT gene with expanded CAG repeats (Petersén et al. 2001). However, the dopamine D2 (dopamine type 2) receptor antagonists could prevent these effects of dopamine in primary cultures of striatal neurons transfected with GFP-tagged exon 1 of the mutant HTT. In this experiment, the D2 receptor agonist was also found to enhance the number of mutant Htt aggregates in the dendrites of neurons and increased cell death (Charvin et al. 2005). As dopamine system is involved in the striatal neuropathology, depletion of striatal dopamine by the 6-hydroxydopamine was shown to be neuroprotective in rodents of HD model via reduction of striatal glutamate (Stack et al. 2007). Considering these observations, tetrabenazine, as an inhibitor of vesicular monoamine transporter (VMAT2) was approved for use in the treatment of HD patients. Tetrabenazine acts by reducing dopaminergic input to the striatum and alleviates the behavioral deficits and neuronal death in the YAC128 mouse model of HD (Tang et al. 2007). In addition, treatment with haloperidol decanoate, a potent D2 antagonist, also protects neurons from expanded Htt-induced dysfunction in the rat striatum (Charvin et al. 2008).

These observations suggest that, manipulation of Htt function by the modulation of dopamine receptors activities may help to inhibit cancer progression. This hypothesis is supported by the fact that, other modulators of the normal Htt protein such as Huntingtin interacting protein (HIP) and huntingtin associated protein (HAP1) are also involved in cancerous cell fate. For instance, in-vitro studies on huntingtin-associated protein 1 (HAP1) , the ligand of Htt that binds more tightly to Htt with an expanded glutamine repeat than to wild type Htt, showed reduced expression in human breast cancer tissues compared to the normal breast tissues. Interestingly, over-expression of HAP1 reduces cell growth in breast cancer cell lines (MDA-MB-231 and MCF-7) and suppresses the cell migration and invasion, and promotes apoptosis in these cell lines (Zhu et al. 2013). These lines of evidence suggest that in addition to Htt and the interlinked dopamine signaling pathway, other huntintin associated genes may also be involved in cancer development and progression, thus could be targeted for cancer therapy.