Moderate Spectrum Genes Associated With Breast Cancer

Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4)

The highly important antitumor response is made up of human cell immunity determined by T lymphocytes and Natural Killer (NK) cells. As a result, gene variations involved in controlling T-lymphocyte and NK cell production will be useful in predicting breast cancer risk. A gene on chromosome 2q33 codes for CTLA- 4 a member of the immunoglobulin superfamily that transmits an inhibitory signal to T lymphocytes. CTLA-4 interacts with B-7 on antigen-presenting cells, and the CTLA-4 gene polymorphism suppresses B-7 surface activity and prevents T-lymphocyte activation [7, 8]. Furthermore, CTLA-4 inhibits immune response [9] as well as tumor-killing activities [10]. CTLA-4 is a four-exon gene that plays a key role in diseases involving T lymphocytes. There have been numerous studies linking polymorphisms in the CTLA-4 gene to autoimmune disorders such as diabetes mellitus type 1, Graves’ disease, Hashimoto thyroiditis, and lupus [11-14], as well as the risk of developing cancer [15]. The link between multiple gene polymorphisms and polygenetic disorders such as diabetes, obesity, and various cancers is gaining traction [16] T cells and Natural Killer Cells (NK cells) play an important role in the fight against cancer [17]. T lymphocytes, particularly T killer cells, play a critical role in protecting cells against malignancies. The CTLA-4 molecule functions as an inhibitor on T-lymphocytes and has a variety of roles in T-cell function. This could hinder T cells from multiplying or potentially trigger apoptosis in activated T cells [18]. The inhibition of tumor immunity by CTLA-4 has been previously demonstrated [10]. A few examinations have shown the job of CTLA-4 bar in upgrading insusceptibility to tumors [19-21].

There are a few reports on the connection between CTLA- 4gene polymorphisms, what’s more, breast malignancy, however, discoveries were clashing [22]. Single nucleotide polymorphisms (1661AG) in the CTLA 4 gene were studied in breast cancer patients and control participants, and their correlations with prognostic variables were analyzed. The goal of this case-control study was to see if there were any links between CTLA-4 polymorphisms AA, AG, and GG and breast cancer risk factors. Genetic differences in breast cancer patients and controls demonstrate that AA and GG genotypes are more frequent in cancer patients, whereas AG genotypes are more common in controls. These findings support the discovery of two more focuses on Iran and China, [23] GG genotype is more common among breast cancer patients, according to this study. In terms of AG genotype, Efrain et al. found no significant differences across their exploration groups. Another study in China discovered that the AG genotype is more common in breast cancer patients [24]. Furthermore, Sun et al., [20] reported that T cells with the AA genotype are less active than those with the GG genotype, and AG is associated with varying levels of malignant development in humans.

PIK3CA

PIK3CA is a gene of 34 kb comprising of 20 exons coding 1,068 amino acids and situated on the 3q26.3 chromosome [25]. The p110 a catalytic subunit of class IA Phosphatidylinositol-3 Kinase (PI3K) phosphorylates phosphatidylinositol-4,5-bisphosphate to produce the second courier Phosphatidylinositol-3,4,5-Trisphosphate (PIP3) at the plasma film encoded by PIK3CA (3q26.3) [26]. AKT, SGK, and PDK1, among other cell stability, expansion, motility, digesting, and angiogenesis-basic proteins, bind to PIP3 and operate on the plasma film. The PI3K/AKT pathway is the most frequently changed route in breast cancer, with PIK3CA alterations being the most well-known of these physical changes occurring at 20–40% recurrence rates [27,28]. When the PIK3CA mutation is expressed in human mammary epithelial cells, it causes constitutive activation of the PI3K/AKT pathway, which results in anchorageindependent proliferation, apoptosis defines, and drug resistance [29]. At two “areas of interest” in exon 9 and exon 20, which encode the helical (E542K and E545K) and kinase (H1047R), over 80% of these mutations happen [30].

Writing regarding the prognostic meaning of PIK3CA mutations is clashing. Gonzalez Angulo et al. discovered an affiliation between PIK3CA and poor prognostic highlights. Li et al., [28] negative discoveries additionally appeared in patients with tumors with PIK3CA changes [31]. Conversely, [32], PEREZ Tenorio et al., [33], and Kolinsky et al., [34] showed there was a link between PIK3CA mutations and better recurrence-free survival. [36] revealed that in patients with PIK3CA mutant tumors, there was an increase in relapse-free survival but no overall survival improvement. [35] and Dupont et al., [37] have shown a huge improvement in without metastasis endurance in PIK3CA mutant breast malignancy patients. In addition to inconsistent prognostic relevance, data on the interaction of PIK3CA mutations with oestrogen/progesterone receptor (ER/PR) expression or human epidermal growth factor receptor 2(HER2) overexpression were also diverse. Numerous bigger populace-based investigations demonstrate a solid relationship of PIK3CA changes with positive ER/PR, negative HER2 tumors [34,32,38].

[35] PIK3CA mutants who were PR positive or HER2 negative had a statistically significant improvement in metastatic-free survival, with a trend toward better survival in ER-positive tumors, compared to ER+ tumors with wild-type PIK3CA. Illogically, the presence of a PIK3CA mutation has been related to protection from anti-oestrogen treatment and proposes a job for mixed treatment with anti-oestrogens and PI3K inhibitors [39,40]. What’s more, HER2-enhanced tumors that likewise harbor PIK3CA changes are less receptive to blends of HER2 inhibitors (trastuzumab/lapatinib and trastuzumab/epratuzumab), adding to the prognostic and helpful importance of PIK3CA mutation testing [35,41]. PIK3CA is the most as often as possible changed quality found in BC and plays a vital role in its turn of events, incorporating a solid relationship with Oestrogen Receptor (ER) articulation and an absence of a relationship with strong actuation of the classical style PI3 K pathway [42,43]. Following the underlying disclosure of PIK3CA mutations in BC, numerous gatherings explored mutational examination to advance the information on hereditary changes that corresponded with BC’s clinic pathological qualities [42]. In breast tumors, PIK3CA changes were reliably connected with receptor-2 (HER2)-positive tumor status of ER-positive and human epidermal development factor [44,46,48]. The relationship between these changes and the anticipation of breast disease is less clear, with a few investigations revealing the relationship between PIK3CA mutations and lymph hub metastasis and more regrettable by and large and breast malignant growth explicit endurance [46,45], while different examinations showed a relationship with longer endurance, especially among patients with ER-positive, HER2- negative tumors [47-49].

KiSS-1

Kiss-1 is a gene that maps to the long arm of chromosome 1 (1q32-q41) and combines four exons, with only the last two partially translated [50]. The gene KiSS1 is made from four exons, the initial two untranslated. Exon 3 incorporates the translational beginning site followed by 103 translated bases, while exon 4 is the biggest with 335 translated bases and 121 non-translated bases [50]. At dibasic locales, for example, R66-R and K123-R, the encoded full-length 145-amino corrosive KiSS1 protein goes through posttranslational cleavage bringing about dynamic 54-amino corrosive peptide metastas or then again kisspeptin-54 (KP54) [51,52]. A few more limited items, overall, called kisspeptins, result from proteolytic cleavage which happens normally. The kisspeptin which holds the last 10 carboxy-terminal amino acids can tie the receptor GPR54 to perform sKiSS1 activities [53]. At first, the Kiss- 1 gene was distinguished as a competitor metastasis silencer in 1996, when its articulation was discovered to be differentially upcontrolled in C8161 melanoma cells delivered nonmetastatic by the microcell-interceded move of an unblemished duplicate of human chromosome 6.

Even though the Kiss-1 gene has been recognized as a solid silencer of metastasis in an assortment of tumors, restricted and clashing information on the interlaced connections between the Kiss-1 framework and breast malignancy has been submitted, and its organic job in this specific disease stays to be explained [54,55]. Kiss-1 was first proposed as a breast cancer metastasis suppressor gene when it was discovered that Kiss-1-transfectant cells inoculated MDAMB-435 in sub-axillary mammary fads of female athymic nude mice suppressed regional lymph node and lung metastasis by at least 95% without affecting tumorigenicity [56]. Another examination directed by Martin et al., nonetheless, showed that the insertion of the Kiss-1 gene into the MDA-MB-231 breast malignancy cell line expanded motility and invasiveness and reduced matrix adhesion, hence giving more metastatic phenotypes [54]. Martin et al. also discovered that Kiss-1 levels in breast cancer tissues were greater than in background tissues and that nodepositive tumors had much higher Kiss-1 levels than node-negative tumors. Kiss-1 expression was also higher in breast cancer patients than in healthy controls, and it increased with increasing grade and TNM status [54]. These outcomes are obviously in the clash with the initially proposed role of Kiss-1 as a metastasis inhibitor in breast disease. Marot et al., [55] also found that Era-positive tumors resected from postmenopausal women treated with TAM had a shorter backslide free endurance (RFS) in combination with higher tumor levels of Kiss-1 and GPR54 mRNA than tumors with lower levels of the two genes [55].

The scientists additionally showed that Kiss-1and GPR54 articulation in breast cancer cells has been contrarily controlled by oestrogen milieu, with ER-positive tumors showing lower levels of Kiss-1 contrasted with ER-negative tumors [55]. Rather than the above outcomes exhibiting Kiss-1as a facilitator of metastasis, Kotadiya et al. discovered that the Kiss-1 gene was silent in a vast majority (97%) of 272 resected stage II or III hubs positive breast adenocarcinomas [57]. Another examination likewise announced that KP-10 can restrain bone-coordinated movement of GPR54- positive MCF-7 breast malignancy cells [58]. In contrast to the high universal staining observed in normal tissue, Pentheroudakis et al. found that barely half of 48 malignancies (52%) were immunoassayed for kisspeptin (40 percent weakly and 12 percent moderately) [59]. In previous studies, increased Kiss1 expression has been linked to advanced tumor grade [54,55] and nodal positivity. Furthermore, lobular carcinomas have higher Kiss-1 expression than ductal carcinomas [54].

PTEN Gene

This novel tumor suppressor gene located on chromosomal band 10q23.3 is known as PTEN (MMAC1-mutated in multiple advanced cancers) [60]. It was recently reported that PTEN/MMAC1 encodes a dual-specificity phosphatase that dephosphorylates Focal Adhesion Kinase (FAK), inhibiting cell migration, spreading, and focal adhesion formation [61,62]. PTEN regulates the 1-phosphatidylinositol 3-Kinase Pathway (PI3K), which is crucial for cell proliferation and survival [63]. Cell line studies in breast cancer have shown that PTEN inhibits their growth by deregulating PI3K, with subsequent G1 arrests and cell death therefore [64,65]. The PTEN gene has been studied in embryonic stem cells and has shown an increased growth rate and early entry into S-phase cells with mutations of the gene [66]. In addition to a rapid G1/S transition, p27 expression was markedly down-regulated, which is indicative of an inhibitor of G1cyclin-dependent kinases. Finally, the findings indicated that PTEN regulates the progression of the cell cycle and cell survival. A genetic mutation in the PTEN gene is also associated with another rare, autosomal-dominant, hereditary disease known as Cowden disease, which increases a woman’s risk of breast cancer by 25 to 50 % over their lifetime.

PTEN mutations in Cowden disease have been associated with breast tumorigenesis in a few studies, but by other investigators, this has not been confirmed [67-69]. Several studies have been conducted to examine the role of PTEN in sporadic breast cancer tumorigenesis. In such studies, PTEN gene mutations have been associated with a small number of cases [70]. In a recent study by Ghoshal al., it was revealed that PTEN functions as a transcriptional repressor, inhibits the cell-mediated survival signaling pathway, and negatively regulates human breast carcinoma cell growth [71]. In various malignancies, mutations at the PTEN locus have been observed, and recent studies indicate that PTEN regulates the growth of breast carcinoma cells [71]. Some studies failed to find the loss of PTEN heterozygosity in breast cancers, which suggests that PTEN may not play an important role in breast cancer development [72]. Researchers have found a significant down-regulation of PTEN expression (48%) in breast cancer. Several studies have found allelic loss of PTEN in 27 of 70 (39%) and 17 of 42 (40%) breast tumors, according to research published previously, another immunohistochemical analysis of 33%of breast cancers examined revealed a poor or negative tumor staining [73]. As a comparison, where the loss of heterozygosity is high (30 to 40%) and mutations predominate in a significant proportion of breast cancer cell lines, primary sporadic cancers are less likely to exhibit mutations [74,75]. On the other hand, PTEN mutations are an occasionally causative factor in familial breast cancer, with lifetime risks over 50% in patients with Cowden’s disease [76,77]. A group of sporadic breast tumors previously analyzed using molecular techniques were also immunohistochemically analyzed to determine if PTEN loss occurred in these cancers [78].

TPD52

It was discovered nearly 20 years ago that the tumor protein D52 gene (TPD52) was over-expressed in human cancer, and a growing body of evidence strongly suggests it may be an amplification target at chromosome 8q21.13 [79]. There have been several investigations that suggest breast cancer is one of the specific cancer types expressing high levels of TPD52 [80,81,82]. Byrne et al. summarized several reports of focal chromosome 8q21.13 amplification involving the TPD52 locus which was specifically observed in breast cancer [83]. A wide genomic analysis demonstrated focal amplification of TPD52 and five adjacent genes on chromosome 8q21.13 associated with breast cancer [84]. TPD52 was identified as a possible driver gene by integrative analysis of the copy number and expression of breast cancers, and they are gradually categorized into a wide range of molecular subtypes, in addition to identifying subtypes associated with TPD52, research is also attempting to refine this molecular taxonomy. One of the most strongly amplified regions on chromosome 8q21.12-q21.13 is associated with the luminal B subtype [86].

The TPD52 gene showed the most significant association between copy number and expression in this amplicon, supported by neighboring locus MRPS28 [85]. Moreover, TPD52 was found to be substantially increased in copy number and expression in luminal B tumors, wherein it was also 1 of the 22 genes whose increased expression was associated with promoter demethylation [87]. A reproducible link between TPD52 expression and ERBB2 expression has been found in human breast cancer cell lines and tissues, as well as in mammary tissues from Erbb2-transgenic mice [88]. The analysis published recently revealed that TPD52 expression was significantly higher in ERBB2-positive diagnostic breast tumors compared with ERBB2-negative tumors, and that relative transcript levels of TPD52 were optimal in the hormone receptor- and ERBB2-positive subgroups [82]. TPD52 expression has been linked to poorer outcomes in breast cancer patients [80, 82], which is consistent with TPD52 expression being linked to both the luminal B subtype [80,81] and ERBB2 expression [82]. As shown in the study above, TPD52 levels across approximately 6% of the diagnostic test cohort were associated with a significantly decreased tumor-free survival [82]. In the TCGA cohort, TPD52- amplified breast cancers were found to be in a similar proportion to that of the breast cancers found to be amplified by TPD52 [84].

Conclusion

In this investigation, we tended to the low range gene changes and their job in breast disease inclination. Even though there are still a significant number of moderate-risk genes to be discovered, its functional implications may remain mysterious precisely because of the polygenic context in which each of them exists. It appears that the clinical relevance of genes associated with moderate-risk breast cancer will remain limited for quite some time. Even though some genes with moderate breast cancer risk carry a limited number of gene variants, others may carry multiple variations. Genes associated with moderate-risk breast cancer cause high disease penetrance only in polygenic settings and can thus not be recognized as gene-related breast cancer predispositions. Understanding these genes associated with tumor genesis and their pathways are basic in the improvement of preventive and restorative systems to battle breast disease.

Acknowledgment

I thank to Mr. Naqash Alam for valuable suggestions on this review article.

Conflict of Interest

None.

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