Cells contain specific sensors to monitor DNA repair and induce apoptotic cell death when the DNA becomes damaged (1). Tumor suppressors serve critical roles in the regulation of the genomic integrity and the DNA repair pathways in various types of cells (2). Increased genomic instability can promote the development of cancer and neurodegenerative diseases, such as Alzheimer's disease (AD). The pathogenesis of these conditions is a multi-step process, accompanied by accumulation of genetic alterations in the somatic cells. In addition, aging contributes significantly to the impairment of physiological gene expression. AD and cancer are both prevalent in the elderly population (3). Although both are age-associated diseases, one is degenerative and the other is proliferative at the cellular level. Various factors that are upregulated to sustain cell growth in any type of cancer may be downregulated in AD-neurons contributing to neurodegeneration. Therefore, it is hypothesized that the inverse relationship between cancer and AD exhibits a reciprocal inverse association in several underlying aspects. Epidemiological data suggest that subjects who develop neurodegenerative diseases due to aging have a decreased risk of cancer (4). As neurodegeneration and carcinogenesis share a number of biological pathways, this inverse association is interesting to explore. The hypothesis proposes that neurodegeneration and carcinogenesis may manifest by several distinctive phenomena associated with senescence (5). The mechanism underlying intrinsic susceptibility of the cells towards either cell proliferative or cell apoptotic outcomes remain unknown (Fig. 1). A full understanding of these pathways may aid in the prevention and treatment of cancer or neurodegeneration (6). At present, effective treatment strategies for both diseases are lacking. The identification of the biological mechanisms responsible for the development of these diseases may provide novel targets for future therapeutic applications.

Cancer cells that originate from the primary site exhibit altered proliferative activity as a result of gene mutations responsible for controlling cellular proliferation. The mutations may result in the upregulation of proto-oncogenes and/or the downregulation of tumor suppressor genes (7,8). It is commonly accepted that ROS are the primary trigger of these carcinogenic mutations (9). In addition, oxidative stress may contribute to cancer progression by affecting genomic instability (9). AD is one of the most notorious neurodegenerative diseases whose hallmarks include neuronal loss and/or dementia (10). The most significant DNA lesion affecting the progression of AD is likely caused by oxidative DNA damage (11). In general, increased levels of DNA damage and downregulation of cellular DNA repair capacity have been associated with age-associated diseases. Accumulation of genomic DNA damage can be caused by increased rates of oxidative-damage, which may exacerbate cancer and/or AD progression. Increased DNA oxidation has been reported in the post-mortem brain tissues of humans with AD (12). It has also been observed that DNA repair is dysregulated in AD (13). A stable increase in ROS levels can lead to potent induction of oxidative stress in cells, which causes genomic instability leading to the development of both diseases (Fig. 1).

The balance between ROS levels and the reducing equivalents in the cell determines the redox status and consequently, cell fate. For example, the therapeutic strategy in cancer should be based on treatments that increase ROS production and cause apoptotic cancer cell death (14). In contrast to this hypothesis, the strategy in treating neurodegenerative diseases should be based on protecting the activity of the neurons against the development of oxidative stress (15). Consequently, the redox status may have prognostic potential for the development of cancer and neurodegenerative diseases. The regulation of the redox status may affect the quality of life of the patients. The production of ROS is regulated by the action of chemical and enzymatic antioxidant systems, including ascorbate and the antioxidant enzymes, such as SOD. SOD enzymes possess a significant antioxidant role characterized by their ability to scavenge ROS (16). It has been demonstrated that SOD defects are associated with the development of several types of disease (17,18). Cytosolic SOD1 serves an important role in reducing the damage to the central nervous system (CNS) (19). Loss of SOD1 increases ROS levels, which triggers the induction of oxidative DNA damage to the cells. Mutations in the SOD1 gene are responsible for causing damage to the mitochondria and ultimately leading to the development of the progressive neurodegenerative diseases, such as familial amyotrophic lateral sclerosis (ALS) (20). It has also been revealed that SOD1-null animals develop specific age-related diseases, such as muscle atrophy (21). SOD2 has been identified by certain studies as a tumor suppressor since its expression is reduced in several types of cancer (22). In addition, the roles of SOD2 are involved in the development of neurodegenerative diseases (23). One of the most significant processes affected by SOD2 activity is the regulation of energy metabolism. Furthermore, SOD2 can protect mitochondrial DNA against oxidative damage. Mitochondrial adenosine triphosphate production activity has been reported to be impaired in AD (24). Mice containing one deleted copy of the SOD2 gene exhibit accelerated progression of AD development (25). SOD2 is localized within the mitochondrial matrix, which is the crucial site of free radical production from the electron transport chain (26). SOD3 exists as a secreted form in the extracellular matrix of several tissues. Downregulation of SOD3 has been shown to alter DNA copy number and/or to promote the hyper-methylation of the promoter DNA region (27). SOD3 is secreted to the extracellular matrix in the CNS tissues. Previous studies have shown that inhibition of ROS production by SOD activation may reduce neuronal cell death and glial cell activation, which may have an unusual effective therapeutic potential compared with conventional treatments (28,29).

Tumor suppressor gene products are molecules which may protect a cell from carcinogenesis (30-36). Accordingly, loss of function in these molecules may be important in the formation of several types of cancer (30,34). Well-studied tumor suppressor molecules include TP53, breast cancer susceptibility gene 1 (BRCA1), phosphatase and tensin homologue deleted on chromosome 10 (PTEN), APC and the retinoblastoma protein (Rb), amongst others (31-36). Mutations in BRCA1 may increase the risk of the development of breast and ovarian cancer (30). Furthermore, it has been shown that the genetic variation in the BRCA1 gene is associated with prostate cancer development (31). Activation of the phosphoinositide 3-kinase (PI3K) enzyme is often associated with the development of BRCA1-associated breast cancer (32). The functional insufficiency of BRCA1 activates the PI3K/AKT oncogenic pathway, which may also be associated with the development of neurodegenerative diseases (33). Reduced levels of BRCA1 have been found in the brains of patients with AD. In addition, knockdown of neuronal BRCA1 has been shown to affect synaptic impairment and memory deficits (34). Accordingly, BRCA1 may support neuronal integrity and cognitive functions, whereas the reduced function of the neuronal BRCA1 contributes to cognitive deficits in AD (35). The changes to DNA repair as a result of BRCA1 mutations may occur early in the progression of neurodegeneration. BRCA1 can bind to BRCA2, Rad50, Rad51 and Rb in order to activate the cell cycle checkpoints (36). Although these protein complexes are present in neurons of the adult cortex and cerebellum, their expression is considerably diminished in the neurons of the brain tissues from AD subjects (37). These complexes may be involved in DNA repair and the regulation of the cell cycle checkpoints (38). The Rb protein is another tumor suppressor involved in cell-cycle regulation and neural cell apoptosis (39,40). Rb is used as a potential diagnostic marker for AD (39,40). The p27^Kip1 and p21^Waf1 proteins are also activated by BRCA1 in AD (41). In addition, mutations of the pathogenic protein presenilin in AD result in a specific increase in the expression levels of p21^Waf1 and in the expression levels of the proteins involved in TP53 signaling (42). The levels of p21^Waf1 are increased in AD. The induction of cell death or cell survival is mediated by the coordinated action of the BRCA1, p21^Waf1 and TP53 proteins dependent on the type of oxidative damage caused by the cells.

The PTEN gene is ubiquitously expressed during embryogenesis in mammals (43). PTEN is a tumor suppressor and its absence may exacerbate prognosis during the early stages of cancer (44). Furthermore, mutations of PTEN underlie certain types of hamartoma tumor syndromes (Cowden syndrome, PTEN-related Proteus syndrome, Proteus-like syndrome, Bannayan-Riley-Ruvalcaba syndrome). These mutations further increase the risk for the development of various types of cancer (45). PTEN deficiency induces a stress on DNA replication, which disturbs mitotic spindle formation leading to an increase in chromosomal instability (46). In addition, PTEN may protect genomic integrity by controlling multiple processes involved in chromosome inheritance-formation (46). Various somatic PTEN mutations in cancer have suggested an involvement of PTEN in the carcinogenesis process. Inactivation of PTEN affects the activation of PI3K/AKT signaling, which induces increased expression of several genes required for cell survival, growth and migration. These genes are all indispensable in cancer development. In contrast to these observations, the induction of PTEN may be associated with the activation of a pathway required for cell apoptosis (47,48). Therefore, neuronal cell death has been attributed, at least in part, to the alterations in the function of PTEN, whereas the inhibition of PTEN may retain synaptic function and improve cognition in AD, as demonstrated in animal models (49,50). Furthermore, overexpression of PTEN results in synaptic depression which mimics the symptoms of Aβ-induced AD (51). It is interesting to note that Aβ recruits PTEN and results in the accumulation of its levels in the postsynaptic compartment (52). The repression of PTEN and/or the stimulation of AKT are important in the protection of the neuron. Furthermore, decreased expression of PTEN may result in an increase in mitochondrial activity associated with high levels of ROS production (53). Extensive induction of oxidative stress caused by environmental factors can result in neurological diseases, including ALS (54). PTEN and PTEN-induced putative kinase 1 may be involved in the pathways of the regulation of cellular oxidative stress. The maintenance of the balance between pro-oxidants and anti-oxidants is required for healthy neurons.

TP53 is a transcription factor ubiquitously expressed in all cell types, which regulates the cell cycle checkpoints and the induction of apoptosis following DNA damage (55). In response to various cellular stresses, activated TP53 may induce cell cycle arrest (56). Failure of the DNA repair machinery to correct extensive DNA damage activates the induction of apoptotic cell death mediated by the TP53 protein (56). The genomic integrity is maintained by the cells decision to induce DNA repair or to activate the apoptotic cascade (57). The TP53 gene is frequently mutated in numerous types of cancer cells, suggesting that it serves a critical role in preventing normal cells from malignant transformation (58). The importance of TP53 as an inherited cancer susceptibility gene product has been demonstrated in Li-Fraumeni syndrome, and is associated with a high risk of developing cancer in multiple types of malignancies (59). The functions of TP53 are supported by different downstream targets and several effectors. Among these, cyclin-dependent kinase (CDK) inhibitors such as p21^Waf1 are important mediators of TP53(60). As mentioned earlier, p21^Waf1 is activated by BRCA1 in AD. Furthermore, the specific severity of the clinical progression of AD is associated with mutation of the presenilin protein into a pathogenic isoform that is frequently observed in patients with AD (42). This mutation may be mediated by p21^Waf1 and TP53 signaling proteins (42). Accumulation of DNA damage irrespective of the TP53 function may also lead to neuronal cell death following AD.

The comprehensive roles of these tumor suppressor signaling molecules can be used to explore the potential inverse associations between AD and cancer. Cell survival or apoptosis may be governed by the balance between DNA damage and repair, which has received increasing attention as a major pathway used in the treatment of cancer and neurodegenerative diseases (61,62).

DNA repair is a multi-step process by which a cell corrects DNA damage (63-66). The DNA repair system firmly sustains genomic fidelity through the recognition and repair of the damaged nucleotides. Therefore, it is likely that carcinogenesis is principally caused by increased DNA damage, and that the dysregulated function of the DNA repair machinery can lead to decreased genomic stability. These phenomena may also be associated with neurodegenerative disorders including AD. As several tumor suppressors serve a crucial role in maintaining genomic stability, the dysregulated or reduced function of the tumor suppressors is associated with increased genomic instability in cells, which consequently accelerates the mutations of other critical genes (63). Deficiency in DNA damage responses and/or downregulation of the DNA repair mechanism results in increased genomic instability. The recognition of DNA damage may rely on the function of ataxia telangiectasia mutated (ATM), which is a cell-cycle checkpoint kinase that phosphorylates various proteins including BRCA1 and TP53 in response to DNA damage (64). BRCA1 associates with Rad50 and Rad51, two types of DNA recombinase enzymes required for genomic stability (65). BRCA1 activates CDK inhibitor p21^Waf1 and TP53, which subsequently adjusts the expression levels of several proteins that control cell-cycle checkpoints, collectively decreasing cell-cycle progression (65). In addition, upregulation of PTEN represses the expression levels of AKT kinase and the activity of murine double minute 2 (MDM2), which enhances the levels of TP53, leading to the induction of cell-cycle arrest or apoptosis (66). MDM2 is an oncoprotein that regulates several tumorigenic proteins, whose mRNA levels are regulated by TP53 in response to DNA damage (66). MDM2 is also involved in the development of neurodegenerative diseases (66). One of the mechanisms by which PTEN induces cell-cycle arrest is by regulating AKT such that the levels of p27^Kip1 are increased (66). BRCA1 is associated with chromosomal stability and spindle formation (67). Previous studies have suggested that the proteins BRCA1 and TP53, and the PTEN and AKT signaling pathways are involved in modifying genomic stability and/or response to DNA damage (66,67). These processes involve additional proteins that interact with each other in a complex network (66,67). Nuclear localization of tumor suppressors mediates several activities of tumor suppression required for genomic stability, which may contain a range of functions including DNA repair and cell cycle arrest. For example, PTEN interacts with histone proteins and controls chromatin function (68). In addition, PTEN regulates the expression of Rad51, which reduces DNA damage (68). It has been suggested that PTEN serves a role in the protection of the cells following induction of oxidative damage (33). The activity of PTEN can be repressed by ROS and the loss of its activity is associated with several types of cancer, which could result from genomic instability (69,70). Furthermore, decreased levels of PTEN are associated with reduced irradiation-resistance, which can be suppressed by ectopic PTEN expression (71). PTEN serves a role in the induction of cell-cycle arrest through activation of ATM signaling. Therefore, knockdown of PTEN increases ATM activation, decreasing the phosphorylation levels of ATM substrates, such as TP53 and BRCA1, which is considered a significant part of the DNA repair signaling cascade (72).

Genomic integrity may be sustained through the function of several tumor suppressor genes, which reduces pathologic alterations, such as the development of carcinogenesis and neurodegeneration. Loss of the function of the tumor suppressor genes may reduce DNA repair and induce genomic instability, which can lead to cell apoptosis. Furthermore, it may enhance the sensitivity of cancer cells to irradiation. With regards to therapeutic applications, this treatment may be beneficial for patients with cancer. Neurodegenerative diseases can be caused by neuronal cell apoptosis of non-proliferative neuronal cells (Fig. 1). The use of alkylating agents and/or irradiation for cancer therapy may promote neurodegeneration due to the genomic instability caused from excess production of ROS (73). In conclusion, the present review reports on the increased number of age-related occult cancer and the reduced potential of anti-oxidative defense mechanisms that would determine the bipolar fates of patients with regard to the development of cancer or of neurodegenerative diseases in elderly individuals (Fig. 2). This may explain why the inverse association occurs in the elderly in contrast to younger patients (Fig. 2). In the absence of the excess ROS production, bacterial inflammation and/or life-style-associated fatty diseases may increase ROS levels in the elderly, which may in turn increase cancer incidence and the induction of neuronal apoptosis. Consequently, the extent of DNA repair capacity would determine the tendency to develop either cancer or neurodegenerative diseases (Fig. 2).

Tumor suppressor genes can act in a cooperative manner to maintain genomic integrity (Fig. 3). The understanding of the complete assembly of the tumor suppressor proteins can aid in the development of effective treatment approaches for cancer and neurodegenerative diseases. Further mechanistic studies are required in order to understand the precise assembly among tumor suppressor proteins and the molecular signaling mechanisms responsible for facilitating the development of effective treatments, which can regulate genomic stability and improve therapeutic efficacy. These factors may influence the development of neurodegeneration and/or regulate cognitive dysfunction in the elderly. Further studies are required to elucidate the biological mechanisms underlying the inverse association between cancer and AD with the goal of identifying preventative molecular targets.