Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer

Lv, Quanxia; Meng, Ziyuan; Yu, Yuanyuan; Jiang, Feng; Guan, Daogang; Liang, Chao; Zhou, Junwei; Lü, Aiping; Zhang, Ge

doi:10.3390/ijms17122095

Cited by 46 publications

(44 citation statements)

References 112 publications

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“…However, HER2 is an orphan receptor that exists constitutively active. The formation of heterodimers or homodimers thereafter activates the intracellular tyrosine kinases and triggers the autophosphorylation of specific tyrosine residues, ending in the activation of signaling cascades, such as PI3K/Akt/mTOR and MAPK [ 71 ]. Although HER2 is vital for normal cell processes, the overexpression of HER2 leads to tumorigenesis.…”

Section: Signaling Studiesmentioning

confidence: 99%

Ganoderma spp.: A Promising Adjuvant Treatment for Breast Cancer

et al. 2017

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For the past several decades, cancer patients in the U.S. have chosen the use of natural products as an alternative or complimentary medicine approach to treat or improve their quality of life via reduction or prevention of the side effects during or after cancer treatment. The genus Ganoderma includes about 80 species of mushrooms, of which several have been used for centuries in traditional Asian medicine for their medicinal properties, including anticancer and immunoregulatory effects. Numerous bioactive compounds seem to be responsible for their healing effects. Among the approximately 400 compounds produced by Ganoderma spp., triterpenes, peptidoglycans and polysaccharides are the major physiologically-active constituents. Ganoderma anticancer effects are attributed to its efficacy in reducing cancer cell survival and growth, as well as by its chemosensitizing role. In vitro and in vivo studies have been conducted in various cancer cells and animal models; however, in this review, we focus on Ganoderma's efficacy on breast cancers. Evidence shows that some species of Ganoderma have great potential as a natural therapeutic for breast cancer. Nevertheless, further studies are needed to investigate their potential in the clinical setting and to translate our basic scientific findings into therapeutic interventions for cancer patients.

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Section: Signaling Studiesmentioning

confidence: 99%

Ganoderma spp.: A Promising Adjuvant Treatment for Breast Cancer

et al. 2017

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“…The human epidermal growth factor 2 (HER2, also called ErbB2) protein is overexpressed in 15-30% of breast cancers and prognoses an aggressive tumor type, resistance to chemotherapy, and an increased mortality rate. The HER2 gene is also amplified in several other cancer types, such as gastric, ovarian and prostate cancers [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…Currently, there are several methods to detect HER2. The most frequently used test is immunohistochemistry (IHC), which is generally verified by fluorescence in situ hybridization (FISH) in the case of unambiguous cases [1]. Though IHC has its advantages (fast and relatively cheap), this semi-quantitative method also has some limitations such as the effects that are produced during sample taking (biopsies) and the lack of common guidelines for staining procedures.…”

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confidence: 99%

Structure–Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy

et al. 2020

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Human epidermal growth factor (HER2) is a transmembrane tyrosine kinase receptor that is frequently overexpressed in breast cancer. Its increased level prognoses a poor patient outcome and a high mortality rate. Despite the widening spectrum of therapies that are becoming available to treat HER2+ breast cancer, its side effects and resistance still make this protein a valuable object of research in targeted tumor therapy. The role of tumor-targeting peptides has become more and more prominent in the last few decades due to their simple synthesis and pharmakokinetic properties. Here, we examine two fluorescently-labeled HER2-specific peptides and their combined analogues that are developed to target the extracellular region of HER2. The peptides are investigated on breast cancer cell lines with different HER2 expression profiles. Moreover, their extracellular localization and specificity are confirmed by flow cytometry and confocal microscopy. Therefore, a new, combined HER2 binding conjugate is obtained that interacts with HER2-overexpressing cells with high affinity and specificity. Furthermore, secondary structure prediction reveals that the α-helical content of the peptides is associated with their receptor recognition. This highly specific conjugate can be used as a starting point for diagnostical or drug-targeting purposes in upcoming studies.Biomolecules 2020, 10, 183 2 of 17 receptors. The only exception is HER2, which does not directly bind to any known ligands [3]. HER2 can form heterodimers with all three other members of the protein family, or, in the case of an elevated receptor concentration (such as the case in cancer), it can be found as homodimers as well. The most potent heterodimer consists of HER2 and HER3, and it is considered to be the most active signaling complex among tyrosine kinase dimers. Upon ligand binding, phosphorylation occurs and activates several downstream signaling pathways: the phosphatidyl-inositol-3 kinase (PI3K) and the Ras/Raf mitogen-activated protein kinase (MAPK) pathways. Consequently, cell proliferation, cell survival and apoptosis inhibition is enhanced [4].Under normal circumstances, HER2 plays a vital role in mitogenic signaling, and the expression level of HER2 remains stable. However, when the overexpression of HER2 occurs, it can disrupt the dynamic balance of many cellular mechanisms and lead to uncontrollable tumor growth because: (i) Overexpression makes excessive HER2 receptors available to form extra heterocomplexes, (ii) HER2 may strengthen the affinity of ligand-binding for other receptors, (iii) HER2 might weaken the specificity of its heterodimerization partners, (iv) HER2-engaged dimerization can activate proliferation and survival, and (v) HER2-containing heterodimers may escape from the internalization or degradation of HER2 dimers. All these processes lead to increased tumorigenesis and metastasis [5,6].Because HER2 has a crucial role in poor breast cancer prognosis, several therapies have been developed in the last decades to target this receptor. ...

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“…From a structural point of view, HER2 is a 1255-amino-acid transmembrane glycoprotein with 185 kDa(7, 8) known for its function as a ligand-less co-receptor. It is noteworthy that HER2 is the only member of the EGFR family that does not homodimerize under normal conditions, and its ectodomain does not directly bind ligands(9). It is activated via heterodimerization with other ligand-bound receptors, with HER3 the preferred heterodimerization partner(10) or homodimerization when it is expressed at very high levels on the cell surface(11).…”

Section: Introductionmentioning

confidence: 99%

Dynamical rearrangement of human epidermal growth factor receptor 2 upon antibody binding: effects on the dimerization

Magalhães

Machuqueiro

Almeida

et al. 2019

Preprint

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23Human epidermal growth factor 2 (HER2) is a ligand-free tyrosine kinase receptor of the HER 24 family that is overexpressed in some of the most aggressive tumours. Treatment of HER2+ breast 25 cancers with the humanized monoclonal anti-HER2 antibody (Trastuzumab) revealed highly 26 effective, encouraging the development of various HER2-specific antibodies, kinase inhibitors 27 and dimerization inhibitors for cancer therapy. Although it is known that HER2 dimerization 28 involves a specific region of its extracellular domain, the so-called "dimerization arm", the 29 mechanism of dimerization inhibition remains uncertain. However, uncovering how antibody 30 interactions lead to inhibition of HER2 dimerization is of key importance in understanding its role 31 in tumour progression and therapy. Herein, we employed several computational modelling 32 techniques for a molecular-level understanding of the interactions between HER and specific anti- 33HER2 antibodies, namely an antigen-binding (Fab) fragment (F0178) and a single chain variable 34 fragment from Trastuzumab (scFv). Specifically, we investigated the effects of antibody-HER2 35interactions on the key residues of "dimerization arm" from molecular dynamics (MD) 36 simulations of unbound HER (in a total of 1 µs), as well as scFv:HER2 and F0178:HER2 37 complexes (for a total of 2.5 µs). A deep surface analysis of HER receptor revealed that the 38 binding of specific anti-HER2 antibodies induced conformational changes both in the interfacial 39 residues, which was expected, and in the ECDII, in particular at the "dimerization arm", which is 40 critical in establishing protein-protein interface (PPI) interactions. Our results support and 41 advance the knowledge on the already described trastuzumab effect on blocking HER2 42 dimerization through synergistic inhibition and/or steric hindrance. Furthermore, our approach 43 offers a new strategy for fine-tuning target activity through allosteric ligands. 45 Keywords 46Breast cancer; dimerization inhibition; human epidermal growth factor 2 (HER2); molecular

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Molecular Mechanisms and Translational Therapies for Human Epidermal Receptor 2 Positive Breast Cancer

Cited by 46 publications

References 112 publications

Ganoderma spp.: A Promising Adjuvant Treatment for Breast Cancer

Ganoderma spp.: A Promising Adjuvant Treatment for Breast Cancer

Structure–Activity Relationship of HER2 Receptor Targeting Peptide and Its Derivatives in Targeted Tumor Therapy

Dynamical rearrangement of human epidermal growth factor receptor 2 upon antibody binding: effects on the dimerization

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