HER2 Receptors in Different Types of Cancer

HER2 Receptors in Different Types of Cancer

Abstract

Human Epidermal growth factor Receptor 2 has tyrosine kinase activity and is primarily found along with various epidermal growth factors. They have a crucial role in increasing the cells present in the epithelium and, later on, the proliferated cells’ angiogenesis. In this paper, the signal transduction of the Human Epidermal growth factor Receptor 2 is critically analyzed along with its role in various types of cancers, including breast cancer, gastrointestinal typically colon cancer and carcinomas in the ovaries. Moreover, the role of Human Epidermal growth factor Receptor 2 in metastasis of the tumors is also discussed. Various genes, typically vascular endothelial growth factor (VEGF) is crucial to tumor cells to vascularize them. The role of vascular endothelial growth factor (VEGF) is also discussed in detail as it acts as a synergist to HER2. The purpose of other genes in the regulation and expression of the HER2 and how they contribute to the oncogenic mutation of the healthy endothelial cells are also discussed.

 

Introduction

Human Epidermal Growth Receptor1,2,3 and four are closely related to the Epidermal Growth Factor Receptor (EGFR) gene. It was first discovered between 1982 to 1984 by a team of scientific researchers at the Massachusetts Institute of Technology right after the groundbreaking discovery of the Epidermal Growth Factor Receptor (EGFR) gene in 1978. Followed by this breakthrough, aggressive experimentation and cloning of the Human Epidermal growth factor Receptor 2 remained a matter of interest for scientists who carried out aggressive experimentation to determine the role of this gene in signal transduction and cell cycle. In 1998, the scientist achieved another milestone by getting approval from the American Society of Clinical Oncology (ASCO) to test for serum HER2 levels for breast cancer. Since then, the role of the HER2 gene expression in various cancers is understudies.

Signal transduction

The proteins of HER family are type 1 Trans-membrane growth receptors that perform the task of activation of the intracellular signaling pathway, which is generated based on the extracellular signals. The structure consists of the following domains:

  • Ligand binding extracellular domain
  • Trans-membrane domain
  • The intracellular tyrosine kinase domain

The functions of the HER family are more complex in the mammals; twelve ligands and four receptors are responsible for the performance of the functions in mammalians, making it more complicated. After the ligand has attached to the extracellular domain, dimerization and transphosphorylation occur in the intracellular domains of HER proteins as shown in Figure 1 below:

 

Figure 1: Signal Cascade facilitated by HER2(Altieri et al., 2013)

Various intracellular signaling molecules are docked by the phosphorylated tyrosine residues, which lead to the activation of a plethora in downstream second messenger pathways. Furthermore, different transmembrane signaling pathways crosstalk with each other, which results in various biological effects. The selection of partners is of utmost importance and determines the signaling activity in HER proteins. A hierarchical district order which selects homodimers over heterodimers is followed by the HER proteins and their signaling functions. The strongest catalytic kinase activity is present in HER2, and the strongest signaling functions are present in the HER2 that consists of a heterodimer within itself. The functional difference that requires dependency instead of independence or terminating functions is associated with the expansion of HER family in the system of mammals. The example of this interdependency is given by explaining the mechanism and structure of HER2 and HER3. Both receptors are functionally incomplete and lacking as compared to the other members of HER family. There is no noticed pivoting action in the HER2 protein, which might enable it to pivot between active and inactive conformations and make it constructively exist in an activated conformation.

Furthermore, the ligand-binding activity in HER2 is absent, and therefore the signaling function is maintained by its partner that is a ligand-bound heterodimer. The HER3, on the other hand, lacks the ability to bind ATP within its catalytic domains and thus making it inactive catalytically. The kinase activities present in the heterodimeric partners of HER3 are responsible for the mediation of its signaling functions. In short, HER2 and HER3 are considered obligate and interdependent partners who are individually incomplete in terms of signaling molecules. When they form a complex, they become the most efficient signaling heterodimers in the family that is deemed important for various biological, developmental, and constructive processes. Through several shreds of evidence, these HER proteins are suggested to be very important for the mammalian system as they are responsible for the buildup organ system in the mammals (Moasser, 2007).

Role of HER2 in Cancers

The overexpression of HER2 receptors is said to be the main cause of various cancers as they are responsible for the buildup of organ systems in our body (Iqbal & Iqbal, 2014). With an in-depth study of the overexpressing abilities of the HER2 receptor, it is clear that its overexpression can occur in the form of several types of cancers like:

  • Breast cancer
  • Esophageal cancer
  • Cervix cancer
  • Colon cancer
  • Bladder cancer
  • Throat cancer
  • Lung, head and neck cancer
  • And various other carcinomas

The over-expression of HER2 causes multiple mutations in the cells. Which later takes the form of malignant and tumors in the body and result in death for the person or specimen. For example, an individual has elevated over-expressive HER2 has a lower survival rate as compared to the individual with a normal rate of HER2 expression. Furthermore, HER2 protein also has been utilized as a therapeutic agent other than its involvement in developing cancers and tumors in various body parts. In some cases, inhibition of HER2 can prevent cancer, and so on (Moasser, 2007)

HER2 in Breast Cancer

According to statistics, the most common overexpression of HER2 in the organs is noticed in the breast, leading to breast cancer. About 15-30% of breast cancers are caused due to overexpressing HER2 receptors. In certain cases, breast cancers can consist of 25-50 copies of the HER2 protein genome, and they may also consist of a 40-100-fold increase involving HER2 protein. This results in the expression of 2 million receptors at the surface of the tumor cells. HER2 signaling activation has been noticed by estrogen as well. The estrogen is working through the nongenomic activity of estrogen receptors established exterior to the nucleus. This activity has shown to activate HER2 signaling. P95 is a peculiar form that has the deficiency of the extracellular domain in itself, is also present in breast cancers. Trastuzumab is a chemotherapeutic drug that attaches to the extracellular domain of HER2. P95 causes resistance to this binding procedure as it is continuously active. This resistive and active nature is also the main reason the antibodies targeting extracellular domains cannot detect p95.

The HER2 expression was concentrated in 704 hub negative breast malignancies. It was discovered that ladies with breast disease consisting of high overexpression had a danger of repeating 9.5 occasions more noteworthy than those who consisted of normal expression in their breast tumors. HER2 enhancement likewise connected essentially with the following:

  • Pathologic phase of ailment
  • Number of axillary hubs with tumor
  • Histologic sort
  • A nonattendance of estrogen receptor (ER)
  • Progesterone receptor (PgR)

Various shreds of evidence suggest that in the development of human breast cancer, the HER2 amplification occurs in the early stages. Furthermore, this amplification is observed in more than half of situ ductal tumors with the absence of evidence pointing out at an invasive disease. HER2 enhanced breast tumors have expanded affectability to certain cytotoxic chemotherapeutic operators and protection from certain hormonal specialists and expanded inclination to metastasize to the cerebrum. Thus, in short, suggesting that the overexpression and the degree of overexpression are responsible for the development and reoccurrence of breast malignancies in Humans (Ishikawa, Ichikawa, Shimizu, Sasaki, Tanabe, Chishima, Takabe, Endo, 2014).

HER2 in Gastric Cancer

About 10-30% of the patients suffering from gastric cancer consisted of overexpression of the HER2 gene. These overexpression associates with the aggression and poor outcome and result of the disease. HER2 protein overexpression in gastric malignancies was first described by using the methodology of immunohistochemistry (IHC) in 1986. In a study relating gastric cancer, Gravalos and Jimeno found out that in the gastroesophageal junction, tumors and tumors consisting of intestinal-type connection included of HER2 overexpression more commonly as compared to other types of gastric cancers. The overexpression of HER2 has a negative effect on gastric cancer, and the overexpression also co-relates with more deficient in gastric malignancies. Furthermore, it was noticed that HER2 staining intensity was related to the following aspects:

  • Tumor size
  • Serosal invasion
  • Lymph node metastases

Additionally, Gastro-oesophageal tumors and intestinal tumors consisted of a higher rate of HER2 positivity. The status of HER2 in gastric cancers is observed through the following methods:

  • IHC
  • FISH
  • Biopsy
  • Surgical specimen

However, unlike breast cancer, the role of HER2 in gastric cancer is not as clear and is still under study as various aspects in this field are still unclear (Boku, 2013).

HER2 in Esophageal Cancer

Recording from 0-83% of esophageal cancer, we observe that the HER2 expression was absent. HER2 overexpression was observed to be present at higher positivity rates in adenocarcinoma calculating from 10-83% as compared to the squamous cell carcinomas that calculated about 0-56% of HER2 overexpression positivity. The HER2 overexpression was associated with the following aspects:

  • Low quantity malignant lumps
  • Fewer invasiveness
  • Presence of Barrett’s esophagus (BE)

Further observation and in-depth studies concluded that HER2 heterogeneity among HER2 intensified EACs was a free indicator of more terrible malignant growth explicit endurance. Esophageal cancer is the sixth most deadly type of cancer, which has taken the lives of almost over 90 percent of its patient. Esophageal cancer usually occurs in combination with gastric cancer, as both are related to the disruption of the digestive system and metabolism. (Gowryshankar, Nagaraja, Eslick, 2014)

HER2 in Ovarian Cancer

About 20-30% of patients that have been diagnosed with ovarian cancer have resulted positive with HER2 overexpression. Berchuck was the first person to establish the connection of HER2 overexpression with a poor survival rate in advanced epithelial malignancy/cancer. From all the patients suffering from ovarian cancers, those whose cancer was caused by HER2 overexpression had a lower rate of survival and a higher rate of reoccurrence as compared to the patients with normal expression. Furthermore, patients with high HER2 overexpression were more resistant to chemotherapeutic drugs and developed a weak response to primary therapy. The patients that possessed EGF receptor mRNA in their tumors were less likely to survive and live on as compared to the patients possessing negative expression tumors. The practicality of therapies directed towards HER2 was noticed to be limited due to low-frequency presence in an intense expression. Furthermore, the patient’s survival rate is indirectly proportional to the strength of the HER2 overexpression, which means the higher the strength of the overexpression, the lesser the chance of survival for the patient. The HER2 overexpression also has a connection with progesterone and estrogen hormones; the increase in overexpression of HER2, and its amplification decreases the estrogen and progesterone levels, which is a major cause that leads to malignancies. (Serrano-Olvera, Dueñas-González, Gallardo-Rincón, Candelaria, Salazar, 2006)

HER2 in Endometrial Cancer

The rates of HER2 overexpression that were reported in endometrial serous carcinoma range between the values of 14-80 percent. If we examine through the methodology of HER2 amplification requiring the procedure of FISH (Fluorescence in situ hybridization), the range reported is 21-47%. In the endometrioid carcinomas, the overexpression and amplification of HER2 have been observed in the range of 1% to 47 percent, and another observation was sighted reporting 0 percent to 38 percent. The poor prognosis is regarding endometrial carcinoma is directly linked to the overexpression and amplification of HER2. Furthermore, the patients suffering from endometrioid carcinoma having high expression and amplitude of HER2 suffered worse with a lower rate of survival as compared to the patients that had a lower amplification and expression rate of HER2.  (Buza, Roque, and Santin 2014)

HER2 in Colon Cancer

The cancer of colon ranks second most dangerous cancer in North America, recording numerous deaths. However, colon cancer can be removed from surgery in the early stages of diagnosis; however, the major issue is that about 20 percent of colon cancers are not detected until they reach stage IV. HER2 plays a major oncogenic role relating to cancer in the body. HER2 is responsible for activating signaling pathways that are responsible for cell survival and cell proliferation. HER2 amplification has also been detected in cancers. There is a direct linkage between the presence of HER2 protein levels and the prognosis of colon cancer. Furthermore, covers on the occurrence of EGFR/HER2 overexpression have been disparate and uncertain because of specialized varieties (Ochs, Wong, Kakani, Neerukonda, Gorske, Rao, Keville, 2004).

HER2 in Other Cancers

The overexpression of HER2 in the lungs has been reported at about 20 percent. Furthermore, mutations regarding HER2 were also reported in lung adenocarcinoma. These mutations were specific in targets, and the following population was the major target of these mutations:

  • Nonsmokers
  • Occasional or light smokers
  • Oriental ethnicity
  • Female gender

If we talk about urothelial bladder cancer, we observe that the HER2 overexpression reported in this diagnosis ranged about 23 percent to 80 percent, and the HER2 amplification range was recorded from 0 percent to 32 percent. Furthermore, disappointing clinical benefits were reported when clinical trials of HER2 directed therapeutics were held targeting the lungs and bladder.

HER2 Positivity in Various Cancers:

In the following table, we’ll observe the HER2 positivity in various cancers detected by IHC (Immunohistochemistry) method:

Type of Cancer HER2 samples that were positive Total samples HER2 positivity percentage
Bladder Malignancy 60 476 12.4%
Breast Tumors 389 3707 10.5%
Colon Cancer 81 4508 1.8%
Esophageal cancer 72 629 11.3%
Gastric cancer 28 581 4.7%

 

RELATIONSHIP OF TUMOR MARKERS WITH HER2

The inverse relationship between estrogen/progesterone receptor and HER2

The female hormone receptors, which include ER and progesterone receptor PR, are very useful in the prediction and analysis of breast cancers. They serve as useful predictive markers for breast cancer. About 70 percent to 95 percent of invasive lobular carcinoma is expressed by ER. Regarding invasive ductal carcinoma, about 70 percent to 80 percent are expressed by ER. In contrast, in the case of the progesterone receptor, it is expressed in invasive breast carcinoma resulting in about 60 percent to 70 percent. The HER2 is indirectly proportional to ER & PR. This means that if HER2 is downregulating, then ER and PR are up-regulating similarly if ER and PR are down-regulating, then HER2 is up-regulating. HER2 enables the hyperactivation of MAPK; this hyperactivation mediates the downregulation of ER. The ER downregulation is also caused due to increased NFkB activity in tumors that are amplified by HER2. We can down-regulate and restore the operations of ER/PR by utilizing HER2 tyrosine kinase inhibitor, or we could also use HER2 specific antibody leading to retraction of HER2 signal transduction. The methodology of comparing the variations existing between ER, PR, and HER2 present in breast malignancy has proven very successful in predicting the clinical and pathological outcomes that are to be developed in the later future (Lal, Tan, Chen, 2005)

Induction of VEGF

There are various preclinical and clinical proofs to help the relationship and connection of angiogenesis in the development of tumors and the spreading of malignant growth in colon as well as other cancers (Ochs et al., 2004). The key angiogenic growth factor in malignancy is called or known as VEGF. It is also called as the most potent pro-angiogenic signal. Greater risk of reoccurring of the tumor is marked by calculating the level of VEGF. If the VEGF level is elevated, then the risk of recurrence is more.

Furthermore, a decreased response is also noticed regarding hormonal and chemotherapy when the VEGF level is elevated. Hence, an effective approach for cancer treatment in such cases is VEGF inhibition, which results in an effective anticancer methodology. HER2 and VEGF are interlinked with one another. This means that if HER2 is positive, then the presence of over-expression of VEGF is also noticed and vice versa. In short, this means that HER2 and VEGF are directly proportional to one another. Furthermore, the biological aggressiveness of the overexpressing HER2 phenotype is observed to be contributed by VEGF.

Therefore, after covering the preclinical and clinical indication given above, we concluded that blocking of HER2 and VEGF would have a more effective result in anti-tumor activity as compared to other methodologies (Le, Mao, Lu, Thornton, Heymach, Sood, Bast, 2008)

Induction of CXCR4

Fusin also referred to as CXCR4 is a chemokine receptor. It is specific for SDF-1 (stromal-derived-factor-1). It was observed that HER2 is positively inter-linked or co-related with CXCR4. HER2 prevents CXCR4 from ligand-induced degradation by inhibiting the CXCR4 ubiquitination. The following two receptors and factors play a major role in breast cancer metastasis to the lungs.

  • CXCR4
  • SDF-1

The up-regulation of CXCR4 contributes to the lung metastasis induced by HER2. This is due to the fact that CXCR4 recruit’s cancer cells to the part of a metastatic organ, which is enriched by SDF-1. Furthermore, phosphorylation of HER2 is enhanced when CXCR4 activates with SDF-1 (ligand).

This important role and contribution of CXCR4 in metastasis of breast cancer make CXCR4 a major target for therapeutics and cure. However, its essential role in therapy hasn’t yet been demonstrated or practiced via any clinical trials. In the animal model, CXCR4 was tested, and the results were that siRNA was utilized to silence CXCR4, which resulted in the blockage of breast cancer metastasis. Furthermore, these blockages lead to the following results:

  • In vitro inhibition of tumor cell growth
  • In vivo abrogation of tumorigenesis of cancer cells

In some instances, CXCR4 is not linked with HER2, instead, and it is independent. Like in ovarian cancer, both factors are independent of each other and had no influence on another and the overall survival (Li, Pan, Wei, Cheng, Zhou, Tan, Hung, 2004).

Suppression of E-cadherin

E-cadherin is involved in epithelial cell to cell adhesion; by nature, it is a transmembranal glycoprotein. When E-cadherin’s functions were studied, it was observed that it is an essential invasion suppressor gene. About 50 percent of invasive ductal carcinomas have been reported to lose their expression of E-cadherin. In the case of invasive lobular carcinoma, it was reported it lost all its E-cadherin expression as compared to ductal carcinoma, which lost 50 percent of E-cadherin expression. The strength of cellular adhesion in tissue depends on E-cadherin; when E-cadherin represses, it leads to loss of strength and disruption of the tumor. This also leads to an increase in migration and invasion. However, there is controversy in the linkage between HER2and E-cadherin in primary tissue, but it is long established that E-cadherin function is disrupted by HER2 via phosphorylation of Beta Catenin. The mechanism behind this disruption is that Beta Catenin and E-cadherin form a complex through the cell to cell adhesion and cytoskeleton. This complex is disrupted by HER2 as HER2 can bind directly to the Beta Catenin and leads to its phosphorylation, which in turn leads to disruption of the complex of E-cadherin and Beta Catenin. To suppress the invasion and metastasis of malignant cells, we inhibit the interaction and linkage between Beta Catenin and HER2 in colon and gastric malignancies (Li, Pan, Wei, Cheng, Zhou, Tan, Hung, 2004)

Treatment of HER2 in Advanced Gastric Cancer

Many studies have concluded that HER2 overexpression is a major cause for the development of advanced gastric cancer. The positive results of HER2 expression can be detected in approximately 20 percent of the patients. Gastric malignancy is more common in men than in women, with a ratio of 2 to 1. Furthermore, gastro-oesophageal cancers and gastric cancers are the most common types of cancer caused by the HER2 receptor’s overexpression. The pattern of HER2 amplification leading to HER2 overexpression is not yet observed in gastric cancer as it is present in breast cancer. Therefore, this major difference can disrupt a few therapeutic procedures in the treatment of gastric cancer. The methodology used for the treatment of breast cancers will need to be revised and rebuilt for gastric malignancies.

For the treatment of advanced gastric cancers, combination therapy was utilized. This therapy involved chemotherapeutic drugs with a combination of Trastuzumab and lapatinib, which were HER2 inhibitors. This experiment was performed in mice with advanced gastric cancers and proved to be successful. However, it is still under progress and in the stage of clinical trials. A few studies of 2005 and 2006 exist, where this combination therapy was applied to Humans, proving to be very successful. However, the final results were not published. This methodology is still under construction and yet to be determined, but it is also the only effective treatment for advanced gastric cancer caused by HER2 amplification and overexpression (Jørgensen, 2010).

Treatment of HER2 Esophageal Cancer

Esophageal cancer is said to be the sixth most dangerous cancer. It is recorded that 90 percent of the people suffering from esophageal cancer end up dying or experience recurrence. Esophageal cancer is prevalent with gastric cancer, as there is a major connection between the body’s gastric and esophageal system. Esophageal cancer is also said to be caused by HER2 overexpression and amplification. The presence of HER2 overexpression in breast cancer has been recorded for a while now, and targeting therapy for its treatment has proven to be useful too. This treatment involved growth stopping agents like Trastuzumab and Lapatinib, which are responsible for containing the HER2 overexpression.

Hence after this, we can conclude that HER2 overexpression can appear in various types of cancers, even esophageal cancer. In this ailment, an alternate scoring framework for deciding overexpression is utilized. Constrained information exists concerning the biological and helpful ramifications of HER2 overexpression in malignant esophageal growth. In order to develop and observe an effective therapy for esophageal cancer, a trial known as ToGa trial was withheld. This trial involved patients that had gastric cancer with addition to gastroesophageal junction tumors that had the presence of overexpression of HER2. The results that were determined were that patients treated with combination therapy of Trastuzumab and chemotherapy based on cisplatin proved much more effective with a better response, generated a better survival rate and it was progression-free as compared to patients who were treated with chemotherapy alone who showed less progress and a lousy survival rate. Therefore, the use of Trastuzumab in HER2 overexpression tumors proved to be useful, and it is used in the treatment of various cancers that involve HER2 overexpression and amplification (Almhanna, Meredith, Hoffe, Shridhar, Coppola, 2013).

Treatment of HER2 in Positive Breast Cancer

Therapies directed on HER2 have made a cure possible for patients suffering from HER2 positive early-stage breast malignancy. But specific observations have concluded that a critical extent of these patients despite everything backslide and die due to breast malignancies. Trastuzumab and lapatinib are HER2 inhibitors that have proved to be useful in breast cancer therapy during the early stages. However, studies are still undergoing to make this methodology more refined, constructed, and optimized. Furthermore, to cure this disease, following approaches and measures are taken and are still under development:

  • monoclonal antibodies
  • small-molecule tyrosine kinase inhibitors that target HER2 and HER family
  • cytotoxic moieties that are linked to antibodies
  • immune-stimulatory peptides
  • targeting the PI3K pathway
  • IGF-1R pathway targeting

These improvements in the understanding of the pathway of HER2 and its connection and communication with other various pathways of the body have led to a road of development of new and unique therapies. Trastuzumab, a monoclonal antibody, and lapatinib, which is a small-molecule tyrosine kinase inhibitor, has shown to be very effective in the treatment of HER2 positive breast malignancies. Furthermore, new agents are also being developed for the treatment of this specific ailment. However, these therapies will also assist in the treatment of various other malignancies caused by HER2 over expressions. Following are some of the agents that are being introduced:

  • Vaccines
  • tyrosine kinase inhibitors
  • modified antibodies
  • agents directed against HER2 and family members
  • agents directed against resistance pathways
  • agents directed against downstream pathways

The agents against resistance or downstream pathways include mTOR, PI3K, IGF-1R, Akt, HSP90, and VEGF. Furthermore, for severe cases, pertuzumab and Trastuzumab have proved effective in curing the breast malignancy in advanced or final stages (Arteaga, Sliwkowski, Osborne, Perez, Puglisi, Gianni, 2011)

Treatment of HER2 in Colon Cancer

It is recognized as the third most common type of cancer. Furthermore, about 50 percent of the patients suffering from colorectal cancer develop metastatic disease recurrence. About 20 percent of HER2 positivity has been recorded in rectal malignancies. About 10 percent overexpression of HER2 has been documented in colorectal malignancies. Furthermore, the detection of another member of the EGF family has also been observed, known as HER3. HER3 is present in about 70 percent of CRC-derived liver metastases. This observation of the involvement of HER3 is important because HER3 inhibitors are being developed and are in clinical trials at the moment. The overexpression of HER2 and the participation of HER3 have been noticed to play a major role in the development of colorectal malignancies and rectal cancers. Therefore, the following treatments are present for CRC. However, some of these are still under clinical trials:

  • Drugs
    • Drugs are being utilized. Drugs such as Trastuzumab, pertuzumab, T-DM1, 5-FU, and Oxaliplatin have proven successful in treating CRCs.
  • Monoclonal antibodies
  • HER2 inhibitors
  • HER3 inhibitors
  • Combination Therapy (Conradi, Spitzner, Metzger, Kisly, Middel, Bohnenberger, Grade, 2019)

Testing/Diagnosis of HER2

Several methods have been developed for the screening and diagnosis of HER2, but about 20 percent of the time, the tests result inaccurate. Due to this inaccuracy record, the American Society of Clinical Oncology (ASCO) and the College of American Pathologists has suggested to us with various methods and guidelines that will assist us in ensuring that the results are 100 percent accurate. The two methods that have been approved for HER2 testing are the following:

  • Immunohistochemistry (IHC)
  • Fluorescence in situ hybridization (FISH)

The presence and the status of HER2 should be determined with more than one test with patients suffering from invasive breast cancers. The individuals suffering from breast cancer should undergo HER2 testing through the IHC method to determine HER2 protein expression. (Iqbal, Iqbal, 2014)

Immunohistochemistry (IHC)

It is a procedure used to determine the amplification and overexpression of HER2. IHC is the most used methodology of immune-staining. It involves the process of exploitation of antibodies that bind specifically to biological tissues. This method, in turn, helps us identify the antigens in the cells of a tissue. This method is widely used in the detection of malignancies and abnormal cells. Immunohistochemistry is additionally broadly utilized in fundamental research to comprehend the dissemination and restriction of biomarkers and differentially communicated proteins in various pieces of biological tissues (Ramos-Vara, Miller 2014)

In breast cancers, the detection of levels of progesterone, estrogen, and HER2 is done by the method of IHC every 6 hours as a part of the treatment. This is done to ensure that the growth of the carcinoma hasn’t spread to other tissues of the body. This is routinely performed. Various studies have further confirmed that IHC is far more accurate in detecting HER2 amplification than various other tests. IHC staining with the assistance of CBE356 proved 3 percent more specific, and about 23 percent more sensitive as compared to HERCEP test in detected HER2 amplification (Ainsworth, 2005).

Figure 2 shows examination of colorectal specimen from an HER2 positive patient. Anti-HER2 antibodies were used to achieve the staining which clearly show a dense stain in the middle while Figure 3 accounts for an HER negative strain with no dense staining anywhere through the sample.

Figure 2: HER2 positive IHC (Yeh et al., 2019)

Figure 3: HER2 negative IHC (Yeh et al., 2019)

Fluorescence in Situ Hybridization (FISH)

It is a molecular cytogenetic technique. It uses specific probes called the fluorescent probes that bind to those parts of nucleic acid with a high degree of sequence complementarity. This procedure was developed in the early 1980s by biomedical researchers. It is used to detect the presence and absence of DNA sequences and chromosomes. Following are some of the tasks FISH procedure can perform:

  • use in genetic counseling
  • use in medicine
  • use in species identification
  • detection and localization of RNA targets
  • circulation of tumor cells
  • assists in defining the spatial-temporal patterns of gene expression (Lal, Salazar, Hudis, Ladanyi, Chen, 2004)

The FISH procedure is majorly used in the detection of abnormal or cancerous cells within the body. The cancer cells that are produced due to the dislocation of the chromosome in the cell are detected by the FISH method as it stains the dislocated chromosome and points out the major reason behind the development of cancer. Similarly, it is also vastly utilized in the detection of HER2 amplification and HER2 overexpression due to these properties. Furthermore, another major advantage of this method is that it doesn’t require actively dividing cells for its detection method. The results from this procedure are obtained within a few days, making it fast, efficient and reliable (Amann, Rudolf; Fuchs, Bernhard, 2008)

Figure 4 shows a FISH analysis where HER2 overexpression is evident with the dense pattern present at the center in colorectal cells. On the other hand, Figure 5 shows negative HER2 results which are evident from the appearance that there is no amplication of the HER2 marked with the anti-HER2 markers.

Figure 4: HER-2 positive FISH analysis (Yeh et al., 2019)

Figure 5: HER-2 negative FISH analysis (Yeh et al., 2019)

HER2 promotes metastases

HER2 inherits the ability to promote metastases in malignancies. As much as it is expressed in metastases, it also encourages that phenotype. An example of this is that individuals suffering from positive HER2 breast cancer have a greater chance of relapse than individuals with disseminated tumor cells that lack immunocytochemically detectable expression of HER2. The presence of HER2 protects against apoptosis. When there is an absence of apoptosis, the cells will continue growing uncontrollably with a low rate of death. This uncontrollable cell’s reproduction leads to metastases.

Furthermore, the chemokine receptor that expresses breast cancer invades extracellular matrix and circulates in the blood and lymphatic vessels. In short, it causes proliferation and produces metastatic tumors. The HER2 expression up-regulates the CXCR4 receptor. This up-regulation develops a link between HER2 and CXCR4, which results in breast tumor metastasis. Furthermore, about 70 percent of cytokeratin cells extracted from the bone marrow showed a presence of overexpression of HER2. The high frequency of HER2 articulation on micrometastatic breast disease cells in the bone marrow recommends that these cells may have been decidedly chosen during beginning times of metastasis (Freudenberg, Wang, Katsumata, Drebin, Nagatomo, Greene, 2009).

Role of HER2 in Angiogenesis

Various studies have shown that development factors and their receptors assume a fundamental work in controlling the expansion of epithelial cells. The abnormalities in expression, development, and activity preset in their proto-oncogene products contribute to the development and maintenance of the phenotype. The human epidermal growth factor receptor two, also known as HER2, is encoded by c-erbB2. This receptor is overexpressed and amplified in various types of malignancies like colorectal, breast, and ovarian cancers. For productive growth and metastasis, the tumor cells must adopt the method of angiogenesis. Furthermore, the overexpression of HER2 and its amplification is believed to be a major cause of various types of malignancies. This means that HER2 is linked with tumor growth and development (KUMAR, 2001).

Angiogenesis is the procedure through which new blood vessels are formed via the proliferation of endothelial cells. This procedure plays a major role in both physiological as well as pathological conditions. Various studies suggest that there is a direct link between tumor growth and angiogenesis. The angiogenic factors are responsible for the stimulation and growth of endothelial cells and for chemotaxis in host organs. Furthermore, angiogenesis depends on the angiogenic factors as well.

The overexpression of HER2 is linked to the following two aspects

  • increased angiogenesis
  • expression of vascular endothelial growth factor (VEGF)

The inhibition of the VEGF pathway leads to the repression and blockage of Tumor growth and VEGF expression. Therefore, in the line of therapeutics, the drugs that inhibit the VEGF pathway or HER2 have proved effective in stopping the growth of tumor cells as there is a direct link between the tumor cells and the VEGF pathway and HER2.

Role of HER2 in Biological and Therapeutic Aspects

HER2 oncogene overexpression in breast malignancies has been liked with a more aggressive disease. This overexpression increases in proliferation, the formation of vessels, and invasiveness. When the malignancy is going through prognosis, a direct connection isn’t established between HER2 and the carcinoma; however, overexpression of HER2 is connected with carcinoma through gene expression. Furthermore, it has been noticed that HER2 is sensitive to anthracyclines, and it has also shown resistance to endocrine-based therapies. This suggested that the hormone receptors and tyrosine kinase receptor introduced two major proliferation pathways that are active during breast malignancy. The outlining point about these pathways is that one of these pathways is sensitive to chemotherapeutic drugs, and the other pathway is sensitive to anti-estrogens. Therefore, it can be said that HER2 provides the most specific targets for specific and effective therapies. Trastuzumab is an effective therapeutic agent. Trastuzumab is a monoclonal antibody targeted against the extracellular domain of HER2; the drawback is that a lot of HER2 driven tumors are not responsive to HER2 driven therapies. This indicates that this therapeutic drug requires a better understanding regarding its mechanism of action and its in vivo administration. Various experimental studies have explained the involvement of HER2 signaling pathways and its connection or linkage with metastasis induction, survival, and proliferation. However, after testing Trastuzumab, it is clear that the methodology of targeting HER2 has proven successful in clinical and therapeutic uses. However, using Trastuzumab with other therapeutic agents to create a combination therapy is still under progress but is expected to assist in treating various carcinomas in the future (Ménard, Pupa, Campiglio, Tagliabue, 2003).

HER2 overexpression and under expression in colon cancer:

In the patients suffering from colon cancer, it is frequently observed that they either have under expression of HER2 or there is overexpression. The expression of HER2 is not only co-linked with the stage of development of cancer, but also with the gender as well. It was frequently observed that the females had a higher frequency of HER2 disturbance. Moreover, stage III cancer patients with colon malignancies had a higher HER2 disturbance; both overexpression as well as under expression.

Gender and HER2 over or under expression:

HER2 expression varies greatly with gender. As shown in Figure 6, HER2 under expression is more common in females than in men. In 43% males, it is observed that development of cancer is accompanied without any amplification of HER2 while in females, there is higher probability of no HER2 amplification.

Figure 6(Data source: Yeh et al., 2019)

Figure 7 shows that overexpression is more common in females very significantly as compared to men. One reason for this could be the fact that HER2 receptors have a close relation with female androgenic hormones such as progesterone and estrogen. Therefore, 83% of females are likely to present a malignancy with HER2 amplification while only 17% men will show higher HER2 levels.

Figure 7(Data source: Yeh et al., 2019)

Cancer stage and HER2 over and under expression:

Figure 8 shows relation between HER2 levels and stages of cancer development. It is observed that HER2 amplification as well as underexpression is more frequent to occur at stage IIIB. While the reason for this is still unknown, the prospective research can possibly answer the co-existence of amplification as well as underexpression simultaneously at stage IIIB and IIIC. The figure also reveals that stage II and IIIA are only characterized by HER2 underexpression and have nothing to do with HER2 amplification.

Figure 8: Cancer Stages and HER2 levels (Data source: Yeh et al., 2019)

 

Involvement of HER2 in DNA Damage

Various patients are suffering from a different kind of cancer when consist of HER2 overexpression and HER2 positivity in them are treated with drugs that target the HER2 pathways. Most of the cancer is caused due to overexpression of HER2 and its amplification. Therefore, HER2 inhibitors and those therapeutic drugs that target HER2 are utilized. The HER2 targeting drugs are utilized in combination with chemotherapy for better results and more chance of survival with a lesser extent of the recurrence. This whole treatment is observed to damage DNA. These treatments rupture the DNA crosslinks, and breakage of stands also occurs. Through ELISA, intra-strand crosslinks produced by cisplatin were observed. Furthermore, similar experiments were done involving the intra-strand crosslinks, but there was no variation between the results and damage was observed nevertheless. However, it was observed that HER2 played a significant role in the repair of DNA damage due to chemotherapeutic drugs when its pathway was allowed to operate. The studies confirmed that the nuclear expression of HER2 was required for the repairing of DNA that was lost due to chemotherapeutic drugs (Di Fiore, Pierce, Kraus, Segatto, King, Aaronson, 1987)

Discussion:

It is evident that HER2 has a key role in the development of malignancies. Like known before, it is not only persistent in the development of breast cancer, as formerly known, but also in other types of cancers such as esophageal, gastric, colon and endometrial cancer as well. Various tumor markers are analyzed with respect to HER2 to accurately diagnose the metastasis. Hormones and signal transducers in the body closely affect the onset of malignancies related to various organs. However, in recent researches, specific focus is being laid on the role of HER2 and colon cancer. HER2 overexpression is directly linked to several types of cancer. Typically, HER2 overexpression boosts angiogenesis which aids the development of vascularization in the malignant cells. Various cancers including colon cancer can be diagnosed using prognostic testing of HER2 levels. Not only that, to further boost the effect of chemotherapy, HER2 suppression can be a useful resort. The clinical outcomes have greatly improved since this discovery and it is constantly under trials to further study the precise relation between colorectal malignancies and the overexpression of HER2. As for now, the prognostic testing for HER2 is considered to be accurate for gastric and breast cancer only. However, there is further scope to have more development in terms of research in relation between HER2 and colon cancer.

Conclusion

After doing an in-depth study of HER2, we conclude that it plays a significant role in the development of tumors and malignancies. Furthermore, it is a leading cause of various types of tumors. The overexpression and amplification of HER2 in different tissues lead to abnormal cells’ abnormal growth, which later on converts to cancer. For the detection of HER2 overexpression, two methods are discussed. These methods are IHC and FISH; they have proved to be successful in detecting the causing agent. The treatment of HER2 type cancers included drugs and agents that targeted the receptor. These agents include HER2 inhibitors and combination therapies. The therapies given to a patient suffering from HER2 type cancers were a combination of HER2 blocking drug and chemotherapeutic drugs. This blocking of the HER2 pathway resulted in a positive outcome and, in short, increased the overall survival rate. However, to this day, experimentation is still under progress regarding HER2; its role in cancer and its permanent treatment will ensure a 100 percent survival rate with no recurrence.

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