Therapeutic Targets In Breast Cancer Signaling: A Review

For women, the most dominant type of cancer is breast cancer and perhaps one of the most recognizedreasons of death. This is a disorder of many distinct traits, many of which are known as positive hormone receptor, human epidermal receptor-2 (HER2+), and three negative breast cancers (TNBC). Drugs that directly target and kill tumors constitute a rapidly-growing form of molecular therapy for cancer patients. Analysis reveals that stable breast tissue cells exhibit receptors which aren't usually present. As a result, it is imperative to cognize the molecular roots of breast cancer and the myriad compromised pathology-related processes and pathways to ensure progresses in early diagnosis and prevention. This study demonstrates essential cellular pathways relevant for breast cancer including improvements in cell proliferation, apoptosis, and hormone balances in breast tissues. On the basis of these notions, we consider how breast cancer is associated to the creation of potentially therapeutic interventions and predictive biomarkers.


INTRODUCTION
Cancer of the breast is the most prevalent form of cancers in females across the world [1], and it is still the leading cause of death [2]. If we talk about prevalence of breast cancer then in Britain 1 out of 12 females are diagnosed with breast cancer [1]. Breast cancer is very common type of cancer in women and 18% cancers are breast cancer of all types of cancer diagnosed in women [1]. In 2021 the incident of breast cancer is going to increase 85 per 100,000 cases [1]. Breast cancer is considered to be the most pronounced and heterogeneous disease affecting both chromosomal and nonchromosomal causes [3]. The genes that target estrogen receptor (ER) and HER2 crosstalk between ER and other signaling networks as well as epigenetic pathways have been proposed to be implicated in hormone tolerance to endocrine therapy [4,5]. With the new advances in molecular biology and immunotherapy, very precise personalized treatments can be adapted to different categories of breast cancers [6,7]. Therapies targeted for breast cancer comprises of substances or drugs which impede with the biochemistry of cells unsettling the growth of cancerous cells [8]. Women's breast cells might overexpress receptors that triggers them to proliferate, metastasize, etc. [9]. It's a heterogeneous disorder, having multiple risk factors such as diet, size, and family background [10]. Breast cancer is categorized according to a specific place of tumor development and gene expression profiling [11]. While alterations in a few primary genes such as BRCA1 and BRCA2 are related with high cancer risk, majority of cancer cases are caused by genetic traits with low penetrance [12]. To recognize the genetic origins of breast cancer is important because it aids in the detection and prevention of malignant growths [13]. In this study, we outline important cellular mechanisms which have been substantially linked to breast cancer, guiding to modifications in cell proliferation, apoptosis, and hormone balances of breast tissues cells [14,15]. We address some possible indications that can detect breast cancer. There were 13.8 lac new cancer cases in 2008 (23% of total) and 458,400 (14% of total) cancer deaths that year [1]. Around 60% of mortalities from breast cancer are prevalent in technologically advanced nations, predominantly Western and Northern Europe, North America, Australia and New Zealand [16]. According to the American Cancer Society, in 2008 out of 182,500 (approx.) American women who are diagnosed with cancer 40,500 died [1,17]. This is why there are various kinds of breast cancer [18]. There are several pre-test considerations of patients into account [19,20]. It has been shown that positive prognosis exists if receptors are high. Centered on the genetic pattern, breast cancer was classified into three types [21]. In the first group were ER or PR positive tumors and in the second group were positive for HER2 with or without ER and PR positivity [22][23][24]. TNBC is diagnosed because you cannot find an expression of the genes ER/PR and HER-2 [25,11]. Receptor signaling pathways play a critical role in the growth and development of breast cancer, inhibition of these receptors is main therapeutic strategy of breast cancer treatment [26].

TYPES OF BREAST CANCER
There are mainly 3 subtypes conditional on the absence or presence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2 (ERBB2; previously HER2): hormone receptor positive/ERBB2 negative (70% of patients), ERBB2 positive (15-20%), and triple-negative (tumors lacking all 3 standard molecular markers; 15%) [1,27]. At the time of diagnosis more than 90% of breast cancer are non-metastatic [28] . For metastatic individuals, the clinical targets would be to cure the illness and avoid recurrence that's why triplenegative breast cancer has much inferior prognosis in contrast to other two forms of breast cancer because of its 5-year survival rate of 55 percent [28] as shown in Fig.  1.

HER2-positive
It is known that 20% of the aggressive breast cancers in the united states are her2 + [29]. Her2 + cancers have the worst prognosis because they respond poorly to hormone therapy and her2 + cancers have greater chance of recurrence [30]. The breast cancer has so many copies of her2 gene, gene which activates the her2 proteins, which can be located on the cancer cells [31]. While in a normal function her2 receptors controls the growth, division and repair of healthy breast cell while in proliferated state the cell division is rapid and uncontrolled due to the excess absorption of substance known as "human epidermal growth factor 2" energizing cell growth [32]. HER2+ breast cancer has same symptoms as that of the other kinds of cancer including protuberance in the breast; breast shape change, pain, engorgement and unusual discharge [33]. Treatment options for HER2+ breast cancer may include combination of surgical procedure, exposure to radiation, chemotherapy and/or administration of targeted therapy such as the immune monoclonal antibody, trastuzumab depending on its stage [34,35].

Therapeutic targets
Systemic treatment for no metastatic breast cancer is focused on subtype: hormone-positive tumor patients undergo endocrine therapy, and a few receive even chemotherapy; ERBB2-positive tumor patients receive ERBB2-oriented antibody therapy paired with chemotherapy, and chemotherapy is provided to patients with triplenegative tumors [28] as shown in Table 2.

Signaling Pathways (Molecular/ Intrinsic) involved in breast cancer development
Important similarities exist between natural growth and molecular cancer progression [43]. Human normal development is closely regulated by complex signal pathway allowing cells to interact with one another and the factors around them [44]. Various of these similar signaling channels are not surprisingly deregulated or discovered by cancer cells and CSCS [45]. Essentially, cancer is triggered by genetic and epigenetic modifications, which enable cells to escape the pathways that govern the proliferation, survival and migration of cells [45]. All of these shifts map signals regulating cell proliferation and division, cell mortality, cell differentiation and destiny and cell motility [45]. Initiating proto-oncogenic mutations can cause these pathways to be hyperactivated, whereas inactivating tumor suppressors gene destroys essential negative signal regulators [45] the emphasis is on the prevalent signaling mechanisms controlling the natural growth of mammary glands and stem cell functions of breast cancer, namely the signals from the oestrogen receptor (er), her2 and canonical wnt.
[46].        [106]. Homo and hetero-oligomers are formed by frizzled receptors which are cell specific and signal specific in their expression.

MAPK pathway
Other mechanism of action involved association of frizzled receptors with other co-receptors [107]. When Wnt protein is absent low level degradation is responsible for maintenance of beta-catenin signaling pool. Glycogen synthase kinase 3 beta (GSK3b) and serine/threonine kinase 1 (CK1) are responsible for phosphorylation of beta-catenin [108]. A complex consists of adenomatous polyposis coli (APC) protein, diversin and axin is main place for phosphorylation of beta-catenin [109]. GBP/Frat-1 is recruited through to dishevelled proteins (Dsh) because degradation of Beta-catenin is prevented upon receipt of wnt signal [104,105]. This leads to displacement of GSK3b from destruction complex [107]. Wnt signaling is mediated by assistance of low density lipoprotein receptor related protein family (LRP5/6) [104,110]. Dsh comes in contact with frodo and beta-arrestin, while effect of Dsh is effected by Dapper because it is antagonist of Dsh [111] (Fig. 6).
A, wnt1/3 binds the g-protein coupled receptor fzd and the tyrosine kinase receptors lrp5/6 to start initiation of signaling pathway [112]. The subsequent signaling complex elevates βcatenin translocation to the core & along these lines drives development period of melanoma, whereby cells separate & multiply on the surface. B, an expansion in wnt5a enacts the non-canonical wnt signaling pathway through fzd and the tyrosine kinase ror2 [104,110]. Downstream effectors, for example, arf6, akt, jnk and pkc drive a change to the vertical development stage, whereby melanoma attack through the dermis and metastasize c. In breast cancer cells, on the other hand, wnt5a signaling activates camkii to promote -catenin corruption, preventing the translation of qualities that promote metastasis and attack [111].

Jak STAT pathway
STATs are proteins in nature that were found in 1988 [113]. IFNs type I's transcription is initiated by them interferon (IFN)-stimulated response elements are bound to it that is a sequence of DNA [114]. In 1992 three labs separately found JAKs, so that they authored the JAKs pathway [115]. The JAK is a word which originates from deceptive god of Romans that concludes two spaces; it has kinase like space & a synergist field [113]. Type I-and II receptors are closely related to JAKs. The receptor dimerization is caused by a ligand known as cytokine & JAKs are initiated [116]. Trans-phosphorylation takes place when tyrosine residues attaches to JAKs and as a result activates it, STATs docking sites are created for recruitment of inactive cytoplasmic translation factors [117]. In the cell biology Phosphorylation is the most widely recognized alteration, they have a significant role in signaling pathways by its controlling action. In the cytoplasm unphosphorylated (OFF) STATs are present. When JAKs are activated they phosphorylates STATs (ON) and STATs dimers, by this docking sites are abandon on receptors. That's why nucleus is translocated & they activate or suppress gene transcription by binding to specific DNA sequence [115]. Serine phosphorylation is independent [118]. Transcriptional potency is enhanced by phosphorylation of serine of STAT, though serine phosphorylation of STAT3 has been accounted in a negative way. P38, Erk and JNK are involved in serine phosphorylation of STATs [119]. The JAK-STAT pathway additionally encourages different cell reactions to assorted types of cell stretch [120]. JAK1, JAK2, JAK3 and TYK2 are four main members of JAKs family (Stark et al., 1998). Every JAK part comprises of a few distinctive fields which are following: N-terminal FERM domain which is named after the discovery of a protein containing this domain (band 4.1, Ezrin, Radixin and Moesin) [121]. 3 sub-domains F1, F2 and F3 are present in FERM domain, which are basically like CoA binding, pleckstrin homology-phosphotyrosine restricting spaces and Ubiquitin [122]. Protein-protein communications are its responsibility, like on its membrane scaffold &adoptor interaction [123].
The SH2 (Src homology 2) contain around 100 residues in its domain for binding of tyrosine.
Dimerization and activation of STATs is done by SH2 domain [124]. On account of homology to Protein Central pseudo kinase domain is named; catalytic function is absent in them, but they perform regulatory function [125]. On C-terminus PTK domain is located. It comprises roughly 250-300 residues and an ATP-restricting site comparing a synergist domain. On special downstream substrates it is responsible for phosphorylation of tyrosine residues [126]. Seven STATs members are included in humans' STAT family: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6 [127]. They have exciting homology in these regions: Unique Nterminus region is involved in STAT activation e.g. dephosphorylation of the STAT interactions or STAT, like formation of tetramer [128]. In protein-protein interactions and nuclear export coiled-coiled domain plays an important role. AStype immunoglobulin fold is present on DNA binding domain and is also found in p53. Sequence-specific binding is assisted by this [129]. TTCN3-4GAAA sequence is recognized in target genes on the promoter region [130].Trans-Activation Domain is abbreviation of C-terminus and very conserved residues of tyrosine are present here [131]. In recruitment of special proteins many discovered varieties are included, like histone deacetylases, DNA polymerase II, etc. [129]. JAKs are activated in response to cytokine binding, and the intracellular region of the receptor is phosphorylated to serve as a docking site for STATs to be recruited & phosphorylated [132]. Through SH2 domain homo and hetero dimerization starts to takes place. StIP protein (STAT Interacting Protein) is related to JAK-STAT pathway. It assists phosphorylation of unphosphorylated STATs. In the nucleus in impor tin α-5 dependent manner phosphorylated STATs are translocated through Ran nuclear import pathway. Dimerized STATs bind to complex DNA sequences at the end of their transition to control transcription of their own target genes. [133]. Anyhow great knowledge is provided about the process of STAT phosphorylation, dephosphorylation of STAT in the nucleus is not completely defined [134][135][136][137][138] (Fig. 7).

CONCLUSION
Not only are these pathways involved in hormone signaling to cancer cells, but these pathways also control cellular roles that impacts the onset and progression of cancer of breast. Signaling pathways are critical for mammary growth, and variations within pi3k pathway are more prevalent in many diseases, such as parkinson's, diabetes type ii, and various forms of cancer. As the multiple dysregulations in key nodes of the multiple pathway are identified as having links with different diseases, identifying particular alterations and knowing their functional significance will permit for more precise selection of medication, having least side effects. It is seen that the MAPK pathway have pivotal part in progression of breast cancer through inducing cell propagation or leading to further pathways.The movement of cell for the interaction within the extracellular world is carried out by JAK-STAT signalling mechanism/pathway. Dysregulation of Wnt signalling can contribute to development of cancer as it governs cellular differentiation and proliferation. Several facets of regulation of these pathways are still under study, particularly regarding the cross talking of these pathways, their effect on former pathways, feedback, tumor microenvironment interactions, cellular metabolism, risk factors, and reaction to drug therapy. Conversely, both of these mechanisms are seen to be in a coordination acting as a network, and a number of potential interventions need to be considered. In this sense, an increasingly thorough analysis of these pathways facilitates the generation of important and transformative knowledge on the molecular basis for gene expression regulation in normal as well as cancerous cells, as well as the nature of cellular contact. Understanding breast cancer progression and incorporating molecular-based methods for quality improvement in diagnostics, prognostics, and care of breast cancer patients necessitates identifying the spectrum of mutations that exist throughout the major signaling pathways, as well as how they interact throughout pathways. In this era of pandemic it has become mandatory to understand all factors which take parts in pathogenesis of breast cancer because cancer patients are more vulnerable to covid-19. So in future our strategy will be simultaneous treatment of breast cancer and covid-19. For this purpose, we will use two in 1 drugs which will show anti-viral and anti-cancer drugs so that we can improve mortality rate by clinical management strategies. This can be done by better understanding of all signaling pathways which are responsible for progression and pathogenesis of breast cancer.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable. 5. Araki