Decoding HER2: Understanding the Role and Therapeutic Potential of HER2 in Cancer

What is Her2?

Definition of Her2

HER2 (also known as HER2/neu or ERBB2) is a protein receptor located on the surface of human cells and belongs to the epidermal growth factor receptor family (EGFR/ErbB family). Its primary function is to regulate cell growth and division. However, in certain cancers, HER2 may become abnormally overexpressed or mutated, leading to uncontrolled cell proliferation and the formation of tumors.

Her2 plays a critical role in various cancers such as breast, ovarian, and stomach cancers. When HER2 is abnormally expressed, it can trigger excessive tumor cell growth, increase invasion and metastasis, and contribute to the aggressive behavior of the cancer. Due to its significance in cancer development, HER2 overexpression is considered a crucial tumor marker that guides the selection of appropriate cancer therapies.

The Structure of HER2

HER2, also known as ErbB2 or neu in rats, is a 185-kDa transmembrane receptor with tyrosine kinase activity initially identified in a rat glioblastoma model. It belongs to the epidermal growth factor receptor (EGFR) family, which includes HER1 (EGFR, ErbB1), HER3 (ErbB3), and HER4 (ErbB4). Each receptor consists of an extracellular binding domain (ECD), a single transmembrane-spanning domain, and a long cytoplasmic tyrosine kinase domain. The ECD is approximately 630 amino acids long and contains four subdomains arranged in a tandem repeat of a two-domain unit. The first and third subdomains (I/L1 and III/L2) have a β-barrel conformation, while the second and fourth subdomains (II/CR1 and IV/CR2) are cysteine-rich [1].

In general, ligand binding to the extracellular region induces receptor dimerization and activates the cytoplasmic kinase, leading to autophosphorylation and initiation of downstream signaling events. Among the EGFR family members, HER2 and HER3 are exceptional. HER3 is kinase-inactive, and HER2 has no identified ligand. Despite lacking a known ligand, HER2 is the preferred partner in heterodimer formation with other HER members.

The structure of HER2.
Fig.1 The structure of HER2.[2]

The Role of HER2 in Cell Biology and Cancer Development

HER2 plays crucial functions in cell physiology and its involvement in cancer development is significant. As a membrane receptor protein, HER2 exhibits the following functions in cellular processes and tumorigenesis:

  1. Cell Proliferation and Growth: Upon activation, HER2 initiates signaling pathways that promote cell proliferation and growth. In normal conditions, HER2 signaling is tightly regulated to maintain a balance between cell growth and proliferation. However, in certain cases, abnormal expression or mutation of HER2 can lead to overactive signaling pathways, resulting in abnormal cell proliferation and contributing to cancer development.
  2. Role in Breast Cancer: HER2's role in breast cancer is of paramount importance. Approximately 15-20% of breast cancer patients have HER2 overexpression or gene mutations, resulting in HER2-positive breast cancer. This subtype is often highly aggressive and fast-growing. Fortunately, HER2-positive breast cancer is treatable with targeted therapies such as Trastuzumab and Lapatinib, which have been widely utilized in HER2-positive breast cancer treatment.
  3. Role in Other Cancers: Besides breast cancer, HER2 also plays a critical role in other cancers, including gastric cancer, ovarian cancer, and lung cancer. In these cancers, HER2 is considered a potential therapeutic target, and ongoing research is focused on developing targeted therapies against HER2 to improve treatment outcomes.

Expression difference of HER2 in normal cells and cancer cells

The expression of HER2 in normal and cancer cells is a critical area of study in cancer research. In normal cells, HER2 expression is tightly regulated to maintain normal cellular growth and differentiation. While some tissues and organs may exhibit slightly higher levels of HER2 expression within the normal range, its role remains focused on preserving cellular function and balance.

Conversely, cancer cells often show abnormal HER2 expression. The most prevalent abnormality is HER2 overexpression or gene amplification, leading to HER2 positivity. In HER2-positive cancer cells, there is an excessive production of HER2 protein, resulting in hyperactive signaling pathways. This contributes to enhanced cell proliferation, growth, and survival, rendering cancer cells highly aggressive and fast-growing.

Aberrant HER2 expression has been identified in various cancers, with breast cancer being the most notable example. Approximately 15-20% of breast cancer patients have HER2-positive breast cancer. Furthermore, abnormal HER2 expression has been detected in other cancer types, including gastric, ovarian, and lung cancers.

The significance of abnormal HER2 expression lies in its potential for targeted cancer therapy. Patients with HER2-positive breast cancer can benefit from HER2-targeted therapies like Trastuzumab (Herceptin) and other anti-HER2 drugs, which have demonstrated significant efficacy in treating HER2-positive breast cancer. Similarly, research is ongoing to explore HER2-targeted treatment strategies for other HER2-positive cancers, offering hope for improved therapeutic outcomes.

HER2 signaling pathway

The HER2 receptor (also known as ErbB2) is a key player in various cellular processes and cancer development. Unlike other members of the epidermal growth factor receptor (EGFR) family, HER2 does not have identified ligands and remains constitutively activated. As a result, it readily forms homo- and heterodimers with other EGFR receptors upon ligand binding.

Among the EGFR heterodimers, the pairing of HER2 with HER3 forms the most active signaling complex, regulating critical cellular processes [4,7,8]. Activation of HER2 and subsequent dimerization lead to the autophosphorylation of specific tyrosine residues, which, in turn, recruit adaptor proteins or enzymes, initiating a series of signaling cascades [9].

HER2 signaling is transduced through two main pathways: the phosphatidylinositol 3-kinase (PI3K)-Akt pathway and the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway [10]. The HER2/HER3 heterodimer predominantly stimulates the PI3K signaling cascade, while all dimers containing HER2 (HER1/HER2, HER2/HER2, HER2/HER3, and HER2/HER4) can activate the Ras/Raf/MAPK pathway [3]. These pathways are well-known for promoting cell proliferation and inhibiting cell apoptosis.

Figure 2 illustrates the schematic representation of the two HER2 signaling pathways. Understanding these pathways is crucial as they play a significant role in cancer development and can be targeted for therapeutic interventions.

Schematic diagram of HER2 signaling pathways.
Fig.2 Schematic diagram of HER2 signaling pathways. [11]

In normal cells, these signaling cascades are primarily terminated through endocytosis of the EGFR receptor-ligand complexes. The EGFR receptors then undergo recycling to the cell surface or degradation by various enzymes. These processes maintain a dynamic balance of physiological outcomes, including cell division, survival, proliferation, and apoptosis. Under normal circumstances, these signaling processes are essential for normal cell growth and do not lead to tumor growth.

HER2-related diseases encompass various types of cancer where HER2 (human epidermal growth factor receptor 2) plays a significant role. These include:

  1. HER2-Positive Breast Cancer: This is the most common form of breast cancer associated with HER2. HER2-positive breast cancer occurs when the HER2 receptor protein is overexpressed on the surface of breast cancer cells. This leads to abnormal cell proliferation and increased aggressiveness. Approximately 15-20% of breast cancer cases are HER2-positive.
  2. HER2-Positive Gastric Cancer: HER2-positive gastric cancer refers to the overexpression of HER2 protein in gastric cancer cells. Although relatively rare, this type of gastric cancer tends to be aggressive with a poorer prognosis. Targeted therapy for HER2-positive gastric cancer is being developed.
  3. HER2-Positive Ovarian Cancer: HER2-positive ovarian cancer is characterized by HER2 overexpression in a small percentage of ovarian cancer cases. Patients with HER2-positive ovarian cancer may have a less favorable prognosis, but targeted therapies are under investigation.
  4. HER2-Positive Esophageal Cancer: In some cases of esophageal cancer, cancer cells express HER2 protein. While HER2-positive esophageal cancer is less common, it is an important subtype to consider.
  5. HER2-Positive Lung Cancer: Abnormal HER2 expression has been observed in some lung cancer patients. Although the prevalence of HER2-positive lung cancer is low, targeted therapy can be a viable treatment option for these patients.

HER2 positivity in the above diseases indicates that the patient's cancer cells express an excessive amount of HER2 protein, providing an opportunity for targeted therapy. Currently, several HER2-targeted drugs, such as Trastuzumab (Herceptin) and Pertuzumab, have been developed and widely used in the treatment of HER2-positive breast cancer. Moreover, ongoing research explores their potential in treating other types of HER2-positive cancers.

Clinical significance of HER2 detection

The clinical significance of HER2 detection is of utmost importance, especially for patients with HER2-related cancers. The following points highlight the significance of HER2 clinical detection:

  1. Tailoring Treatment Plans: HER2 clinical testing plays a crucial role in determining the most appropriate treatment plan for patients with HER2-positive cancers, like breast cancer. Traditional chemotherapy may not be as effective for HER2-positive cancers, but targeted therapies, such as trastuzumab, show promising results. Detecting HER2 status helps guide whether to use targeted therapy alone or in combination with chemotherapy.
  2. Predicting Treatment Efficacy: HER2 clinical test results can predict the response to targeted therapy. HER2-positive patients are usually more sensitive to targeted therapy drugs. By detecting HER2 status, doctors can predict how patients will respond to targeted therapy, allowing for treatment plan adjustments to improve effectiveness.
  3. Prognosis Assessment: HER2 status is closely linked to patient prognosis. HER2-positive patients may face a higher risk of tumor invasion and recurrence. Detecting HER2 status helps evaluate patient prognosis and informs appropriate treatment measures.
  4. Monitoring Treatment Efficacy: For patients undergoing targeted therapy, Her2 clinical detection is useful for monitoring treatment effectiveness. A decrease in HER2 expression indicates treatment success, while minimal change suggests ineffective treatment.
  5. Support for Clinical Research: HER2 clinical test results provide valuable references for clinical research. Accurate understanding of patients' HER2 status is vital for recruiting suitable participants for clinical trials and evaluating the efficacy of new therapeutic drugs targeting HER2-related diseases.

In summary, HER2 clinical detection holds great significance in guiding treatment selection for HER2-related diseases, predicting treatment efficacy, and evaluating patient prognosis. It empowers healthcare professionals to design more individualized and precise treatment strategies for patients.

HER2 Protein

Recombinant Human Her2 / ERBB2 Protein

Reference:

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