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Tumorigenesis and Tumour Permissive Phenotypes

Info: 10118 words (40 pages) Introduction
Published: 1st Feb 2022

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Tagged: HealthCancer


Aging, human illness and carcinogenesis

Over the last 20 years, it has become increasingly clear that the incidence of solid tumors in human is strongly correlated with aging. In fact, the increase of age is significantly associated for solid tumor carcinogenesis from somatic cells (Ershler and Longo, 1997a). As the age of an organism increases, the incidence of cancer increases. Therefore, cancer has been regarded as an aging-related disease. The curve for cancer incidence starts with an initial flat shape, followed by an inflection point around the age of fifty, from which the incidence of cancer begins to rise exponentially. Based on these observations, it seems reasonable to suggest that there might be possible alterations in certain biological processes and/or cellular reparative pathways that occur at this inflection point, resulting in tumor permissive phenotypes or phenotypes that favor carcinogenesis (Tao et al., 2014).

Aging is a universal process that can be summarized as a decrease in fertility and survival probability. However, the quantification of aging remains relatively undetermined and elusive. To investigate aging-related processes, measuring patterns of longevity seems necessary. The curve of longevity measures how an organism survives over time statistically and illustrates the survival probability across different lifespans. Although the maximum lifespan between species varies enormously, a common pattern emerges from longevity curves across various species ranging from C. elegans to humans (Guarente, 2007; Tao et al., 2014; Zhu et al., 2014). The shape of the C. elegans longevity curve is very similar to the curve of human cancer incidence. It starts with a relatively flat initial slope, representing the initial high survival probability, and followed by an inflection point at roughly two to three weeks, after which the slope of the curve changes rapidly, representing a steep decline in the probability of survival before the maximal longevity of C. elegans.

The overall pattern of an inflection point that occurs before the steep slope appears seems to be present in the survival curve of most species. Even though the curves for survival and the incidence of human cancers are inverted, the same pattern is evident: both starts with a flat slope followed by a sharp transition to a steep slope marked by an inflection point (Tao et al., 2014). This raises rather interesting questions: 1) Do the inherent cellular reparative biological processes or genes that are directly related to longevity play a role in the observed increased incidence of solid tumors? 2) For these processes and/or genes, are there alterations of enzymatic activities/gene expressions at the inflection point?

Sirtuins as an aging related protein family that directs the cellular acetylome

Sirtuins (homolog of yeast Sir2) were initially discovered in yeast and C. elegans,and these genes play a critical role in extending the life cycle by suppressing toxic rDNA formation, suggesting a potential role of sirtuins in anti-aging (Guarente, 2007). In addition, it has been shown that the interaction between Sir2 and Ku is required for DNA double-stranded break repair (Boulton and Jackson, 1998). Therefore, loss of sirtuins may play a significant role in the control of the life cycle. Furthermore, analysis of the C. elegans longevity data has suggested that the survival rate of C. elegans has an inflection point that indicates a steep decrease in C. elegans survival (Guarente and Kenyon, 2000; Zhu et al., 2014). Overexpression of sirtuins in C. elegans can shift the inflection point to the right, prolonging their life span; whereas knocking out sirtuins in C. elegans can shift the inflection point to the left, reducing their life span (Guarente and Kenyon, 2000).

Mammalian sirtuins, the class III histone deacetylase family, are different from conventional class I and II histone deacetylases (HDACs) (Donmez and Guarente, 2010; Saunders and Verdin, 2009). Mammalian sirtuins share homology with yeast silent information regulator 2 (Sir2) and use nicotinamide adenine dinucleotide (NAD+) as a cofactor. Seven sirtuins (SIRT1–SIRT7) have been found in humans and localized in different cellular compartments. SIRT1, SIRT6 and SIRT7 are nuclear sirtuins, which function as a regulator of several important transcription factors related to cellular metabolism (Finkel et al., 2009; Guarente, 2008), with SIRT1 being the most intensively studied sirtuin in the nucleus. Studies have investigated whether the loss of a specific sirtuin gene can affect mice life span. Mice, lacking one of the seven sirtuin genes (except Sirt6), do exhibit murine physiological phenotypes similar to that observed in humans for several age-related illnesses, including insulin resistance, cardiovascular disease, neurodegeneration, and most importantly tumorigenesis permissive phenotypes  (Donmez and Guarente, 2010; Saunders and Verdin, 2009).

It was first discovered in 2001 that SIRT1 can deacetylate p53 (Vaziri et al., 2001). During DNA damage, SIRT1 is overexpressed and interacts with p53. This results in the deacetylation of p53 at lysine 382, inactivating p53 as a transcription factor. This discovery suggests that during DNA damage response, SIRT1 can inhibit p53 function through deacetylation, therefore reversing damage-induced transcription and reducing the possibility of apoptosis (Vaziri et al., 2001). Later, many other publications have shown that SIRT1 functions to repress the activation of different transcription factors. For example, SIRT1 binds to Hairy-related proteins (bHLH) and represses transcription (Takata and Ishikawa, 2003). Under stress conditions, SIRT1 regulates FOXO transcription factor by increasing its ability of cell cycle arrest and decreasing FOXO3-induced cell death, suggesting that SIRT1 functions to increase longevity by inhibiting apoptosis and increasing stress resistance (Brunet et al., 2004).  SIRT1 also binds to forkhead transcription factor and inhibits forkhead-dependent apoptosis, suggesting that SIRT1 can down-regulate different damage-responsive proteins. All these are initial discoveries show SIRT1 increases lifespan through repression of regulation of transcription factors and/or activation of transcription repressors.

Sirtuin proteins dysregulation and their roles in carcinogenesis

More recent discoveries have suggested that SIRT1 may function as a double-sided coin in carcinogenesis, either by suppressing tumor growth or promoting carcinogenesis and resistance to chemo/radiotherapy. There are many publications suggesting that SIRT1 functions as a tumor suppressor protein. SIRT1 fucntions as a tumor suppressor protein in human papillomaviruses (HPV) by regulation E1-E2 mediated DNA replication. Knocking out SIRT1 results in an increase of replication through acetylation and increased stabilization of E2 protein (Das et al., 2017). As a metabolic protein, SIRT1 can regulate glutamine metabolism (Ren et al., 2017). Haploinsufficiency of SIRT1 elevates c-Myc expression, promoting utilization of glutamine, proliferation and tumor cell growth (Ren et al., 2017). In mesenchymal stem cells, overexpression of SIRT1 inhibits breast cancer and prostate cancer cell growth by recruiting nature killer cells and macrophages, suggesting the potential role of SIRT1 in regulating the tumor inflammatory microenvironment (Yu et al., 2016b; Yu et al., 2016c).

On the contrary, there are also many publications indicating SIRT1 as a protein that promotes oncogenesis. For example, hypermethylated in cancer 1 (HIC1) is a transcription factor that functions with p53 and suppresses cancer growth in mice (Chen et al., 2005). However, inactivation of HIC1 results in SIRT1 upregulation and allows cancer cells to bypass DNA damage-induced apoptosis (Chen et al., 2005). Therefore, it is hypothesized that upregulation of SIRT1 may result in an increase of tumor incidence in mammalians cells. Treatment of oxaliplatin, a chemotherapy reagent, functions to inhibit SIRT1-induced p53 deacetylation, activating apoptosis and reducing cyclin D expression. This results in an elongation of the cell cycle and decreases tumor cell proliferation (Chen et al., 2017).

SIRT1 has also been shown as a potential indicator of advanced pathological parameter in gastric cancer, and high Beclin-1 and SIRT1 expression correlates with a worse clinical outcome and shorter overall survival (Qiu et al., 2016). In addition, another study in gastric cancer has shown that overexpression of SIRT1 and phosphorylated STAT3 (p-STAT3) is associated with a worse clinical outcome in gastric cancer patients, as advanced stage gastric cancer patients have a higher SIRT1 and p-STAT3 staining. While almost every single protein has dual functions related to carcinogenesis/pathogenesis, it is hypothesized that depending on the type of cancer, SIRT1 may have different functions either as a tumor suppressor protein or as a protein that potentially promotes tumorigenesis.

The only cytoplasmic sirtuin, SIRT2, has similar functions as SIRT1, as it can also provide control over cell cycle progression and genomic stability. For example, loss of SIRT2 results in mammary tumors in female mice and hepatocellular carcinoma (HCC) in male mice. SIRT2 regulates the activity of the anaphase-promoting complex/cyclosome (APC/C) through deacetylation of the APC/C coactivators. Therefore, loss of SIRT2 results in increased mitosis, increased genomic instability, and aneuploidy (Kim et al., 2011). These are all phenotypes observed in different types of cancer, and staining of breast and HCC patient samples suggest that compared with normal tissues, SIRT2 is reduced in tumor samples (Kim et al., 2011).

In addition, SIRT2 deacetylates and inactivates the peroxidase activity of peroxiredoxin (Prdx-1), therefore sensitizing cancer cells to DNA damage and cytotoxicity (Fiskus et al., 2016). Furthermore, SIRT2 was downregulated in serous ovarian carcinoma (SOC). Inhibition of SIRT2 in SOC cells results in an increase in tumor cell migration and invasion (Du et al., 2017). Metabolically, loss of SIRT2 results in increased acetylation of PKM2, inhibiting active, tetrameric PKM2 formation and promoting tumorigenesis in Sirt2-/- mammary tumor cells and HeLa cancer cells by inhibiting oxidative phosphorylation and promoting glycolysis (Park et al., 2016b).

However, there are other discoveries suggesting potential roles of SIRT2 in promoting different types of cancer. For example, a study in melanoma suggests that SIRT2 was upregulated in samples with lymph node metastasis (Wilking-Busch et al., 2017). In addition, SIRT2 was found to be upregulated in non-small cell lung cancer cell (NSCLC), and degradation of SIRT2 results in an inhibition of NSCLC growth (Luo et al., 2017). Moreover, overexpression of SIRT2 was found in basal-like breast cancer, as well as deactylating Slug protein at lysine 116 and preventing Slug degradation, and overexpression of Slug protein is associated with basal-like breast cancer aggressiveness (Zhou et al., 2016).

While initial discoveries have suggested that SIRT2 localizes in the cytoplasm and is mainly involved in the regulation of cellular mitosis (Kim et al., 2011; Park et al., 2012), a recent discovery from our laboratory has provided a potentially novel localization of SIRT2, as it can localize in the mitochondria and control autophagy, energy utilization and redox homeostasis (Liu et al., 2016). Specifically, loss of Sirt2 results in an increase of pan-acetylation in mice mitochondrial extracts, suggesting its potential role in regulating mitochondrial acetylation/deacetylation process (Liu et al., 2016). Loss of Sirt2 results in an increase of GSSG:GSH ratio and mitochondrial ROS, suggesting that loss of Sirt2 could create an environment that leads to redox imbalance. Furthermore, loss of Sirt2 decreases cellular respiration capacity, ATP turnover and cellular detoxification, suggesting that SIRT2 may affect metabolic properties as well (Liu et al., 2016). In addition, SIRT2 interacts with many mitochondrial proteins, including SIRT3, suggesting that a potential crosstalk between different sirtuins localized in different cellular compartments may potentially exist.

SIRT3 dysregulation, aberrant intracellular acetylation, and carcinogenesis

Among the sirtuins that are localized in the mitochondria (SIRT3, SIRT4 and SIRT5), SIRT3 is the primary mitochondrial deacetylase (Lombard et al., 2007) and has been demonstrated to be a legitimate tumor suppressor by regulating mitochondrial energy metabolism (Hirschey et al., 2010), limiting the accumulation of mitochondrial ROS (Ahn et al., 2008; Kim et al., 2010). Admittedly, there are discoveries suggesting SIRT3 as a protein that promotes tumorigenesis in gastric cancer and non-small cell lung cancer (Cui et al., 2015; Xiong et al., 2017); however, most discoveries related to SIRT3 suggest that SIRT3 functions as tumor suppressor protein. Because of the mitochondrial localization of SIRT3, one possible explanation why loss of SIRT3 enzymatic activity results in tumor permissive phenotypes can be explained through the aberrant metabolic properties due to loss of SIRT3.

Many additional studies have suggested that SIRT3 plays a critical role in maintaining mitochondrial metabolism homeostasis through its deacetylation activity. It is has been suggested that SIRT3 can regulate mitochondrial energy homeostasis proteins including acetyl-coenzyme A synthetase, long-chain acyl-coenzyme A dehydrogenase, and 3-hydroxy-3-methylglutaryl coenzyme A synthase 2 to respond to nutrient stress (Fritz et al., 2012; Hirschey et al., 2010; Jing et al., 2011; Zhu et al., 2012). SIRT3 also deacetylates ATP synthase F1 complex specifically at lysine 139 of Oligomycin sensitivity-conferring protein (OSCP), and deacetylation of OSCP lysine 139 increases ATP production and mitochondrial energy homeostasis efficiency.

Sixty years ago, Otto Warburg described that tumor cells tend to have aberrant mitochondrial metabolism with a dysregulation of ATP production and mitochondrial energy homeostasis, where cancer cells exhibit higher levels of glucose consumption as compared to their normal counterparts (Warburg, 1956). In this regard, Finley et al have shown that cells lacking Sirt3 exhibit increased glucose consumption (Finley et al., 2011). Loss of Sirt3 increased the stabilization of HIF-1α protein, which functions as a transcription factor that activates multiple cellular pathways including metabolic reprogramming and cancer cell proliferation (Haigis et al., 2012). Loss of Sirt3 increased glucose uptake and lactate production, whereas overexpression of SIRT3 proteins decreased lactate production and suppressed the Warburg effects in cancer cells (Finley et al., 2011).

In addition, it has been shown that loss of Sirt3 increased mitochondrial ROS levels, which increases genomic instability, activates HIF-1α and promotes carcinogenesis (Bell et al., 2011; Haigis et al., 2012; Kim et al., 2010; Tao et al., 2010). Similarly, Ozden et al also suggested that loss of SIRT3 enzymatic activity could affect the pyruvate dehydrogenase enzymatic activity and thus promote the cell to a more transformed phenotype and prefer glycolysis (Ozden et al., 2014). These results provide a potential mechanistic link between mitochondrial acetylome, aging, carcinogenesis.

SIRT3 regulation of cellular oxidation / reduction status and/or reactive oxygen species

It is well known that ROS production is closely linked to the mitochondrial energy metabolism and carcinogenesis. As a result of using oxygen to generate ATP, mitochondria produce ROS as a byproduct. Electrons transfer through oxidative phosphorylation (OXPHOS) constitutes a major way of ROS production, since electrons can leak out of complexes I and III, resulting in one-electron reductions of oxygen to produce the superoxide radical (Spitz et al., 2004). Loss of Sirt3 induced increased acetylation of electron transport chain proteins induced higher steady-state levels of ROS (Finley et al., 2011; Vassilopoulos et al., 2014).

Not only is SIRT3 involved in ROS production process, it is recently recognized that SIRT3 could also directly regulate the ROS detoxification enzymatic activity through deacetylation of (Manganese superoxide dismutase) (MnSOD) and NADPH production through deacetylation of Isocitrate dehydrogenase 2 (IDH2). On this topic, several studies have demonstrated that MnSOD and IDH2 contain several reversible acetyl lysines and that acetylation alters its enzymatic function (Chen et al., 2011; Qiu et al., 2010; Someya et al., 2010; Tao et al., 2010; Yu et al., 2012).Two mitochondrial target proteins, MnSOD and IDH2, both of which are SIRT3 deacetylation targets, become the main focus of my thesis research, as both are critical regulators for cellular redox balance and detoxification processes.

MnSOD was previously regarded as a simple ROS scavenging enzyme with its activity thought to be only stoichiometrically dependent on the levels of mitochondrial superoxide. However, recent studies have been suggested that MnSOD activity could be regulated by several cellular mechanisms including, transcriptional, translational, and perhaps most importantly, post-translational regulation, depending on the intracellular signals or environmental triggers (Dhar and St Clair, 2012; Hitchler et al., 2008; Huang et al., 1999; Li et al., 2006).

Furthermore, intracellular sensing proteins recognizing specific intracellular physiological conditions and initiating post-translational signaling cascades has been known as a fundamental paradigm in biology (Bisht et al., 2003; Gius et al., 1999a; Gius et al., 1999b; Hallahan et al., 1993). Lysine acetylation has recently been regarded as an important post-translational modification mechanism that regulates mitochondrial proteins (Choudhary et al., 2009; Kim et al., 2006; Kouzarides, 2000; Lombard et al., 2007). In this regard, it is logical to hypothesize that MnSOD may contain specific lysine residues, which can be deacetylated by SIRT3.

On this topic, three seminal papers have been published to illustrate how Sirt3 could directly affect MnSOD activity through site-specific deacetylation (Chen et al., 2011; Qiu et al., 2010; Tao et al., 2010). Tao et al. showed that lysine 122 of MnSOD can be targeted for deacetylation by Sirt3. When examining the 3D protein structure of MnSOD, lysine 122 is located near the entrance to the MnSOD inner catalytic core. The data presented in this paper provide significant experimental data to validate the electrostatic facilitation model proposed by Dr. Fridovich (Benovic et al., 1983; Tao et al., 2010; Zhu et al., 2012). Using site-directed mutagenesis, lysine 122 was mutated to an arginine (positive charge mimicking a deacetylated state, MnSODK122R).

This mutation induced higher level of MnSOD activity and decreased mitochondrial superoxide level. In contrast, when lysine 122 was mutated to a glutamine (neutral charge mimicking an acetylated state, MnSODK122Q), MnSOD activity was decreased and mitochondrial superoxide level increased. Given the positively charged lysine residue 122 is located close to the entrance of the catalytic core and ideally oriented to provide superoxide anion attraction. Thus it is reasonable to propose the mechanism of increased MnSOD enzymatic activity is due to the attraction of the negatively charged superoxide anion toward the positively charged lysine residues. However, when lysine 122 is acetylated, the electrostatic funnel shows a neutral to negative charge, which repels superoxide anion, therefore, decreasing the possibility of superoxide entering the active site to H2O2 conversion.

In addition, the role of MnSOD lysine 122 acetylation in carcinogenesis was confirmed by experiments that infection of Sirt3-/- MEFs with lenti-MnSODK122R but not lenti-MnSODK122Q inhibited in vitro immortalization by an oncogene Ras, or exposure to irradiation (Tao et al., 2010).

Similarly, MnSOD lysine 68 was also suggested to be a potential deacetylation site guided by SIRT3 (Chen et al., 2011). Results showed that SIRT3 was able to deacetylate MnSOD at lysine 68 and further increase the enzymatic activity of MnSOD. It is also shown that when cells challenged with DMNQ, a reagent that is known to increase mitochondria ROS level, Sirt3 can be stimulated and further lead to MnSOD activation by deacetylation and protect cells from increased intracellular mitochondrial ROS. All these studies showed that SIRT3 could physically interact with MnSOD and deacetylate MnSOD in cell-free, in vitro, and in vivo (murine) model systems.

In addition, loss of SIRT3 in different cell lines resulted in increased intracellular and mitochondrial superoxide levels, whereas overexpression of WT SIRT3 but not the deacetylation-null, decreased cellular ROS and mitochondrial superoxide levels (Kim et al., 2010; Tao et al., 2010). The deacetylation of lysine 68 and 122 significantly increases the MnSOD enzymatic activity and thus protecting cells from ROS induced genomic instability and other deleterious effects (Chen et al., 2011; Jing et al., 2011; Tao et al., 2010).

In addition, it is now well documented that MnSOD activity is decreased in early breast cancer and several sources have demonstrated that MnSOD plays a critical role in breast cancer cell proliferation, as well as metastasis through controlling the superoxide and hydrogen peroxide production to activate several redox-sensitive survival and proliferation related cell signaling pathways (Becuwe et al., 2014; Kaewpila et al., 2008; Kattan et al., 2008; Li et al., 1995; Sarsour et al., 2012; Vera-Ramirez et al., 2011; Wang et al., 2005)

IDH2, another mitochondrial protein, has been shown to be a SIRT3 deacetylation target. IDH2 was regarded as an enzyme that functions in the TCA cycle. Its primary role is to oxidize isocitrate into alpha-ketoglutarate (α-KG). The active form of IDH2 is a homodimer that binds to isocitrate and NADP+ and catalyzes the production of α-KG and NADPH. NADPH is long regarded as a reducing reagent that functions to remove ROS and reproduce GSH for cellular detoxification (Rush et al., 1985). Therefore, IDH2 is regarded as a critical metabolic and detoxification enzyme in the TCA cycle that supports mitochondrial integrity and energy homeostasis.

On the other hand, genetic loss of IDH2 in mice has been associated with mitochondrial dysfunction, neurotoxicity, and potentially cardiac hypertrophy and Parkinson’s disease (Kim et al., 2016; Ku et al., 2015; Park et al., 2016a), suggesting the role of IDH2 in mitochondrial metabolism and pathogenesis due to dysregulated mitochondrial energy homeostasis and/or detoxification.

Loss of SIRT3 enzymatic activity results in an increase of IDH2 acetylation at lysine 413. Loss of IDH2 enzymatic activity due to acetylation of IDH2 at lysine 413 increases GSSG / GSH ratio, increases mitochondrial ROS levels, and is associated with B cell malignancy (Yu et al., 2016a; Yu et al., 2012). Furthermore, studies also suggested that the induction of deacetylation activity also appears to protect against the development of age-related human pathology, including carcinogensis (Kim et al., 2010; Someya et al., 2010). Thus, with these results, it is logical to propose that SIRT3 functions as a sensing or fidelity protein which can regulate downstream targets through post-translational modifications involving protein acetylation to modify cellular metabolism and redox balance and may be involved in aging-related diseases like cancer.

Three seminal papers have been published to illustrate how SIRT3 could directly affect IDH2 activity through site-specific deacetylation (Yu et al., 2012). It was first shown that caloric restriction (CR) extends the lifespan of mice by activating SIRT3 and IDH2. Activation of IDH2 and SIRT3 by CR reduced oxidative stresses in mice and prevented acute hearing loss. In addition, overexpression of SIRT3 increased NADPH levels and protects cells from oxidative stress (Someya et al., 2010). Later, Yu et al. showed that lysine 413 of IDH2 can be targeted for deacetylation by SIRT3. When examining the 3D protein structure of IDH2, lysine 413 is located near the catalytic NADP+ binding site of IDH2. Using site-directed mutagenesis, lysine 413 was mutated to an arginine (positive charge mimicking a deacetylated state, IDH2K413R). This mutation induced higher levels of IDH2 activity and decreased mitochondrial superoxide levels.

In contrast, when lysine 413 was mutated to a glutamine (neutral charge mimicking an acetylated state, IDH2K413Q), IDH2 activity significantly decreased, the Km value for isocitrate and NADP+ binding significantly increased, the Vmax decreased, and the GSSG / GSH ratio significantly increased (Yu et al., 2012). Thus, it is reasonable to propose that the mechanism of decreased IDH2 enzymatic activity is that when lysine 413 is acetylated, the inability to bind to NADP+ and isocitrate decreases the association of IDH2 monomeric proteins, and therefore decreases the formation of IDH2 homodimers.

Several years later, Yu et al. published another manuscript suggesting that loss of SIRT3 enzymatic activity provides a growth advantage for malignant B cells (Yu et al., 2016a). They discovered that in malignant B cells, SIRT3 protein levels and SIRT3 mRNA levels were lower compared to normal B cells, resulting in a higher IDH2 acetylation levels and a higher Ki67 percentage. In addition, these cells possess higher mitochondrial ROS levels. All these pathological and biochemical phenotypes provide a growth advantage for B cell malignancy. Overall, all these properties associated with loss of SIRT3 enzymatic activity and IDH2 acetylation at lysine 413 suggest that dysregulated IDH2 acetylation, due to loss of SIRT3 enzymatic activity, can provide at least partial explanations of tumor permissive phenotypes and/or tumorigenesis related to Sirt3 loss.

Overall, cells lacking Sirt3 may have dysfunctional coordination of both mitochondrial energy metabolism and detoxification enzymes, which can ultimately result in aberrant and potentially damaging ROS production that may have deleterious biological effects. All these results related to SIRT3, mitochondrial energy homeostasis, ROS production and detoxification also raise several important questions regarding the role of SIRT3 in carcinogenesis that include: (1) what are the roles of sirtuins, specifically SIRT3, in tumorigenesis? (2) how are sirtuins, specifically SIRT3, involved in regulation of cancer cell metabolism, proliferation and metastasis through site-specific acetylation/deacetylation?

SIRT3 is a breast cancer tumor suppressor protein

While mice lacking one of the seven sirtuin genes do not exhibit changes in life span, these mice exhibit physiological phenotypes for several age-related illness, including insulin resistance, cardiovascular disease, neurodegeneration, and most importantly a tumorigenesis permissive phenotype (Desouki et al., 2014). Recently, the Gius laboratory created a Sirt3 knock-out mouse model, and these mice not only exhibit dysregulated mitochondrial detoxification pathways but also contain increased cellular and mitochondrial reactive oxygen species (ROS). In addition, the mice lacking Sirt3 develop estrogen receptor positive (ER+) mammary tumors that display high Ki-67 and are poorly differentiated with poor prognosis, and this histopathology is similar to that observed in women with luminal B breast malignancies (Desouki et al., 2014; Kim et al., 2010; Tao et al., 2010).

Breast cancer is the most common and frequent cancer among women in the US, and it is the second cause of cancer death in women worldwide (Fadoukhair et al., 2015; Lumachi et al., 2015). The expected number of new breast cancer cases in the US is approximately 231800 in 2015, which accounts for 29% of all cancers (Lumachi et al., 2015). Breast cancers are categorized into four different subtypes with different molecular characteristics: luminal A, luminal B, HER2 and triple negative breast cancer (Perou et al., 2000). The luminal A and luminal B breast cancer are hormone-receptor positive breast cancers (Fadoukhair et al., 2015).

Specifically, the estrogen receptor (ER) and/or progesterone receptor (PR) are expressed in both luminal A and luminal B breast cancer, the latter showing high (more than 14% positive using IHC staining) proliferation signature gene expression (Ki67) and/or oncogenic human epidermal growth factor receptor 2 (HER2) expression (Goldhirsch et al., 2011; Mitri et al., 2012; Perez et al., 2015). HER2 and triple-negative breast cancer are hormone-receptor negative breast cancers, with the former showing HER2 overexpression, and triple negative regarded as the most aggressive breast cancer (Goldhirsch et al., 2011).

Receptor positive breast cancer (luminal A and luminal B) accounts for approximately 80% of all breast cancers (Lumachi et al., 2015). Endocrine therapy has been mainly used in receptor positive breast cancer treatment (Lumachi et al., 2015). There are several endocrine therapy methods, including ovarian function suppression (OFS), selective estrogen receptor modulators or down-regulators (SERMs or SERDs) and aromatase inhibitors (AIs) (Lumachi et al., 2015). OFS is used to suppress ovarian function, which secretes estrogen and progesterone (Love et al., 2015).  Surgical removal of ovaries and gonadotropin-releasing hormone agonists (GnRHa) has been used to obtain OFS (Lumachi et al., 2015; Vitek et al., 2014).

The most well-known SERM is tamoxifen (TAM), which blocks ER signaling in the breast and brain selectively (Lumachi et al., 2013; Lumachi et al., 2015). TAM mainly benefits ER+ breast cancer patients by reducing the recurrence and mortality rate (Early Breast Cancer Trialists’ Collaborative et al., 2011; Lumachi et al., 2015). Fulvestrant is the only SERD approved by the FDA (Lumachi et al., 2015). It functions as an ER antagonist with no estrogen agonist activity, binding to ER and preventing ER dimerization and relocalization (Croxtall and McKeage, 2011; Dauvois et al., 1993). AIs inhibit the cytochrome P450 component of the aromatase enzyme complex to prevent estrogen biosynthesis (Mokbel, 2002).

Despite the similarity in the treatment between luminal A and luminal B breast cancer, given the impact of proliferative and oncogenic genes in luminal B breast cancer, luminal B patients have a worse clinical outcome than luminal A patients (Goldhirsch et al., 2011; Perou et al., 2000). Pathologically, luminal B patients have a worse tumor grade and a larger tumor size than luminal A patients (Carey et al., 2006; Haque et al., 2012). Genetically, luminal B patients have a higher p53 mutation rate compared to luminal A patients, resulting in poor prognosis (Carey et al., 2006; Haque et al., 2012). Statistically, luminal B patients have a lower probability of five-year relapse-free survival rate, disease specific survival rate, overall survival rate and distant metastasis-free survival rate compared to luminal A breast cancer patients (Creighton, 2012; Jenkins et al., 2014; Parker et al., 2009).

In addition, higher Ki67 expression found in luminal B breast cancer patients is correlated with higher relapse rate (Ellis et al., 2008). Because of its proliferative characteristics, luminal B breast cancer has become less responsive to chemotherapy and endocrine therapy, and approximately 30% of receptor positive breast cancer did not benefit from endocrine therapy at all (Allred et al., 2004; Creighton, 2012).

Receptor negative breast cancers, including HER2 and triple negative breast cancers, typically have a worse clinical outcome. Metastasis to brain is higher in these two breast cancer subtypes, and patients with HER2 or triple negative breast cancer have a lower survival rate (Martin et al., 2017). Despite the differences of breast cancer subtypes, all four types of breast cancer share a similarity with many other types of cancer, as cancer is an aging-related disease. The data for solid tumors in human suggest that as the age increases, an inflection point that indicates an exponential increase in human cancer incidence occurs after 50 years old (Zhu et al., 2014). Approximately half of the newly diagnosed breast cancer patients are older than 65 years (Barginear et al., 2014; Siegel et al., 2012).

Furthermore, luminal B breast cancer patients older than 60 years have a two-fold increase in luminal B incidence compared to patients between 40 and 59 years old, whereas the incidence of luminal A breast cancer remains relatively constant among different age groups (Creighton, 2012). Therefore, the incidence of luminal B breast cancer is linked with aging and aging related genes. One evolutionally preserved aging-related gene that can result in luminal B breast cancer incidence is sirtuins.

To further understand the role of SIRT3 in breast carcinogenesis, our laboratory has shown that Sirt3 knock out mouse embryonic fibroblasts (MEFs) exhibited significantly higher levels of genomic instability and could be immortalized by infection with a single oncogene, either Myc or Ras.  In addition, these immortalized MEFs were able to grow in low density, soft agar and become tumorigenic in nude mice (Kim et al., 2010). These results strongly suggest that loss of Sirt3 results in a tumor-permissive phenotype in mice. More importantly, Sirt3-/- mice developed mammary gland tumors over 24 months, while no Sirt3+/+ mice developed mammary tumors during the same period.

Interestingly, Histological H&E and immunohistochemistry (IHC) staining identified these tumors as estrogen receptor and progesterone receptor (ER/PR) positive. These results further suggested that Sirt3-/- mice developed mammary gland tumors parallel a well-differentiated, receptor-positive histological characteristic that is commonly observed in breast malignancies in older women (Kim et al., 2010). Finally, using human breast cancer sample sets including SIRT3 expression and Sirt3 RNA levels also showed that SIRT3 expression was significantly lower in breast cancer samples as compared to normal control and negatively correlates breast cancer malignancy (Kim et al., 2010). Together, results from in vitro, in vivo and human studies strongly support the hypothesis that SIRT3 is a genomic expressed, mitochondrial localized tumor suppressor protein.

More importantly, sirtuins have been suggested to play a role in anti-aging and receptor positive breast cancer are most common in post-menopausal women, which incidence increases slowly until the mid 60’s when a significant increase in incidence is observed (Ershler and Longo, 1997a, b). In this regard, results of Sirt3 knockout mice developing ER-positive breast cancer provide a convincing argument that SIRT3 may function as critical regulators at the crossroads between metabolic regulations, aging and aging related human diseases like breast cancer, and loss of Sirt3 would contribute to creating a tumor permissive environment.

Therefore, in my thesis, the overarching goal is to study how does the aberrant acetylation of mitochondrial proteins (IDH2 and MnSOD), due to loss of SIRT3 enzymatic activity, can result in an inbalanced redox environment and energy homeostasis, therefore promoting tumorigenesis and tumor permissive phenotypes.


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