Human Epidermal Growth Factor Receptor-2 Receptor Research Articles

Molecular Docking and Molecular Dynamic Simulation on the Interaction of Saffron’s Active Compunds with HER-2 Protein

Human epidermal growth factor receptor-2 (HER-2) is an essential oncogene in breast cancer. HER-2 causes 25% of breast cancer, and this type of cancer tends to grow and spread faster than others but had a good response to HER-2 targeted therapy. This study aims to analyze chemical compounds in saffron plants (Crocus sativus) that potential to breast anticancer activity by inhibiting HER-2 receptor (PDB ID: 3RCD). The study employed in silico research such as molecular docking using AutoDock Tools software, and visualization with Biovia Discovery Studio. In addition, molecular dynamic simulation was conducted using GROMACS software, with visualization performed using Grace. The molecular docking results showed that Crocetin has a lower binding energy value of -8.37 kcal/mol compared to Herceptin, which is -7.11 kcal/mol and the lowest energy among Saffron bioactive compounds. These results indicated that the affinity of Crocetin in binding to HER-2 receptor is better than Herceptin. The molecular interactions were hydrogen, hydrophobic, electrostatic, and unfavorable bonds. The MD results showed that the RMSD value meets the 0.2-0.5 nm stability requirements. According to the data analysis, Herceptin appears to have a more stable RMSF value when compares to Crocetin. The Rg graph of both complexes showed stability until the end of the simulation. The H-bond results show that the Herceptin complex has more hydrogen bonds than the Crocetin complex. These results showed that the chemical components of saffron plants have the potential as breast anticancers by inhibiting the HER-2 receptor.Keywords: anticancer, Crocus sativus, HER-2 receptor, molecular docking, molecular dynamic.

Abstract 967: Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer

Abstract Background: Human epidermal growth factor receptor-2 (HER2) and hormone receptors are typically used as binary biomarkers for selecting breast cancer therapy. There is a need to explore the clinical relevance of these biomarkers as continuous variables. This is particularly relevant for the new class of antibody-drug conjugates (ADC), in which a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Methods: Clinical and laboratory data from 57 breast cancers collected by the COTA real-world data company were used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with reported HER2 and estrogen receptor (ER) IHC and FISH results. Results: RNA levels accurately reflected and predicted HER2 amplification (see table below). Importantly, RNA data showed significant variation and overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression-free survival (PFS). Similarly, the ESR1 RNA levels accurately reflected ER status and demonstrated significant variation between positive cases. RNA data also showed significant variations in the AR levels. Patients wssith high AR mRNA levels had significantly better PFS (P=0.05). Patients expressing high ER and AR levels had significantly better PFS than those expressing low ESR1 and AR levels (P=0.03). Conclusions: These findings suggest that RNA analysis using NGS is an alternative to IHC and FISH. RNA provides continuous data that can determine cut-off points predicting response to therapy and should be explored in predicting ADC response. ERBB2 mRNA levels (FPKM) in various HER2 IHC groupss IHC Score Valid N Mean Median Minimum Maximum Quartile Range Std.Dev. Zero 19 231 243 63 537 170 110 Zero vs one 3 151 155 45 253 208 104 Zero to one vs one 18 397 302 172 845 365 222 One Vs two 13 495 423 159 1094 273 284 Two vs three 4 7523 7649 937 13859 7183 5310 Citation Format: Maher Albitar, Andre Goy, Andrew Pecora, Deena Graham, Donna Donna McNamara, Ahmad Ahmad Charifa, Andrew IP, Wanlong Ma, Stanley Waintraub. Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 967.

Statins enhance the efficacy of HER2-targeting radioligand therapy in drug-resistant gastric cancers

Human epidermal growth factor receptor2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [177Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [177Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [177Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [177Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.

Evaluation of Receptor Relationships of Some Drugs Used in the Treatment of COVID-19 by Modeling Studies

Objective: It is important to investigate the interactions of drugs used in the treatment process of COVID-19 with cellular mechanisms. In this study, the aim was to investigate the interactions of Dexamethasone, Favipiravir, and Hydroxychloroquine drugs used in the treatment of COVID-19 with the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Materials and Methods: Within the scope of the study, firstly, 3-dimensional structures of receptors and drug molecules were formed. Then the interactions of each of the receptor and drug molecules at the binding site were examined by molecular docking studies, which is a computer-aided drug design method, and their binding affinities were evaluated. Results: As a result of the analyses, it was determined that the drug named Hydroxychloroquine has the highest and the drug called Dexamethasone has the lowest binding affinity for all three receptors. In addition, it has been determined that Dexamethasone develops inappropriate interactions with ER and HER2 receptor active site amino acids. Conclusions: In this study, preliminary data on how receptor interactions can occur when normal individuals and breast cancer patients use Dexamethasone, Favipiravir, and Hydroxychloroquine are presented.

Tailoring the Treatment of Early-stage HER2-positive Breast Cancer: One Size Does Not Fit All

Human epidermal growth factor receptor-2 (HER2)-positive breast cancer accounts for 15% of all breast cancers and this cancer subtype was historically associated with poor outcomes. The development of HER2-directed therapies has dramatically improved outcomes for patients with early and advanced HER2+ disease. Trastuzumab is a HER2-targeted monoclonal antibody first approved for the treatment of advanced breast cancer in the late 1990s. Since then, it has been shown to improve long-term outcomes for patients with early-stage disease, particularly when given in combination with chemotherapy in the (neo)adjuvant setting. Pertuzumab is another monoclonal antibody that targets a different domain of the HER2 receptor from trastuzumab and prevents HER2–HER3 dimerization. The addition of pertuzumab to trastuzumab and chemotherapy improved long-term outcomes for patients with advanced disease; this drug has also been studied in the (neo)adjuvant setting and proved to improve long-term outcomes for patients with lymph node involvement. Neratinib and trastuzumab emtansine in the adjuvant setting have been shown to improve outcomes for selected high-risk patients. As more effective treatment options have been developed for the treatment of HER2+ breast cancer, we have progressively moved from a one-size-fits-all approach towards a tailored paradigm. In this narrative review, we summarize the diagnosis and prognosis of early-stage HER2+ breast cancer, as well as current treatment approaches.

Molecular Docking of Michelia alba Leaves Active Compounds Against Human Epidermal Growth Factor Receptor 2 (HER-2)

Breast cancer characterized by overexpression of the human epidermal growth factor receptor-2 (HER-2) and is a deadly disease worldwide. Chemotherapy with drugs targeting HER-2 is less effective and shows various drawbacks. This study aimed to study anticancer potential of active compounds contained in Michelia alba through molecular docking against HER-2. The molecular docking study was performed toward HER-2 receptor (PDB: 3PP0) containing 30Q native ligand with MCULE. The results showed that cis-linalool oxide, trans-linalool oxide, linalool, β-elemena, α-humulene, and nerolidol contained in M. alba leaves had lower docking scores than quercetin as control. Nerolidol showed the lowest docking score among all compounds. The active compounds in the leaves of M. alba have the potential as a HER-2 inhibitor in silico.

The production of the first functional antibody mimetic in higher plants: the chloroplast makes the DARPin G3 for HER2 imaging in oncology

BackgroundDesigned mimetic molecules are attractive tools in biopharmaceuticals and synthetic biology. They require mass and functional production for the assessment of upcoming challenges in the near future. The DARPin family is considered a mimetic pharmaceutical peptide group with high affinity binding to specific targets. DARPin G3 is designed to bind to the HER2 (human epidermal growth factor receptor 2) tyrosine kinase receptor. Overexpression of HER2 is common in some cancers, including breast cancer, and can be used as a prognostic and predictive tool for cancer. The chloroplasts are cost-effective alternatives, equal to, and sometimes better than, bacterial, yeast, or mammalian expression systems. This research examined the possibility of the production of the first antibody mimetic, DARPin G3, in tobacco chloroplasts for HER2 imaging in oncology.ResultsThe chloroplast specific DARPin G3 expression cassette was constructed and transformed into N. tabacum chloroplasts. PCR and Southern blot analysis confirmed integration of transgenes as well as chloroplastic and cellular homoplasmy. The Western blot analysis and ELISA confirmed the production of DARPin G3 at the commercial scale and high dose with the rate of 20.2% in leaf TSP and 33.7% in chloroplast TSP. The functional analysis by ELISA confirmed the binding of IMAC purified chloroplast-made DARPin G3 to the extracellular domain of the HER2 receptor with highly effective picomolar affinities. The carcinoma cellular studies by flow cytometry and immunofluorescence microscopy confirmed the correct functioning by the specific binding of the chloroplast-made DARPin G3 to the HER2 receptor on the surface of HER2-positive cancer cell lines.ConclusionThe efficient functional bioactive production of DARPin G3 in chloroplasts led us to introduce plant chloroplasts as the site of efficient production of the first antibody mimetic molecules. This report, as the first case of the cost-effective production of mimetic molecules, enables researchers in pharmaceuticals, synthetic biology, and bio-molecular engineering to develop tool boxes by producing new molecular substitutes for diverse purposes.

The HERPET study: Imaging HER2 expression in breast cancer with the novel PET tracer [18F]GE-226, a first-in-patient study.

3069 Background: Over-expression the human epidermal growth factor receptor-2 (HER2) is seen in 20% of breast cancers; this is an adverse prognostic factor and used to guide therapy selection. At present HER2 expression can only be determined using biopsy material using immunohistochemistry or fluorescence in situ hybridisation. Heterogeneous expression of HER2 is now being recognised as a cause of treatment resistance but is difficult to characterise. A non-invasive method for determining HER2 expression could have several advantages and help select appropriate therapy for patients. GE-226 is a novel radiolabelled GE-Affibody radioligand which binds to the HER2 receptor with high affinity at a different epitope than trastuzumab. Methods: Patients with locally advanced or metastatic breast cancer were recruited and scanned for 65 mins after iv injection of 200MBq of GE-226 (mean activity injected for each patient 202MBq (range 164-223MBq, mean radiochemical purity 94%) of radioligand, over one bed position for dynamic imaging, followed by a half-body scan. Blood sampling was used to measure metabolism of the tracer. Safety was assessed. HER2-extracellular domain (ECD) domain was measured in blood. Tumoural uptake was quantified by semi-quantitative and fquantitative parameters in HER2 positive and HER2 negative tumours. Patients had routine baseline FDG imaging. Results: Twenty patients completed the study. GE-226 scans were well tolerated. There were no serious adverse events. GE-226 was slowly metabolised into a single metabolite in the liver; 97% of parent remained at 60 minutes post injection (range 82-100). There was a significant difference in tumoural radioligand uptake between biopsy proven HER2 positive and HER2 negative tumoural patients as measured by SUVmean and SUVmax (p < 0.001). Comparing HER2 positive to HER2 negative cases, there was also a significant difference between tumour to normal tissue uptake ratios SUVmean. Heterogeneous uptake was observed in three patients, two with interlesional uptake variation and one with intralesional heterogeneity. Tumoural uptake increased over time. Normal physiological uptake in salivary glands and the thyroid gland was noted. GE-226 was able to differentiate between lymphadenopathy due to sarcoidosis and cancer in one patient and was superior to FDG which had shown widespread uptake in the benign and malignant nodes. Conclusions: [18F]GE-226 imaging is well tolerated and shows promise for imaging of HER2 positive breast cancer. Further studies with this agent are now planned. Clinical trial information: NCT03827317.

Unusual Patterns of HER2 Expression in Breast Cancer: Insights and Perspectives.

The biomarker human epidermal growth factor receptor-2 (HER2) has represented the best example of successful targeted therapy in breast cancer patients. Based on the concept of "oncogene addiction," we have learnt how to identify patients likely benefitting from anti-HER2 agents. Since HER2 gene amplification leads to marked overexpression of the HER2 receptors on the cell membrane, immunohistochemistry with clinically validated antibodies and scoring system based on intensity and completeness of the membranous expression constitute the screening method to separate negative (score 0/1+) and positive (score 3+) carcinomas and to identify those tumours with complete yet only moderate HER2 expression (score 2+, equivocal carcinomas), which need to be investigated further in terms of gene status to confirm the presence of a loop of oncogene addiction. This process has demanded quality controls and led to recommendations by Scientific Societies, which pathologists routinely need to follow to guarantee reproducibility. In this review, we will span from the description of classical HER2 evaluation to the discussion of those scenarios in which HER2 expression is unusual and/or difficult to define. We will dissect HER2 heterogeneity, HER2 conversion from primary to relapsed/metastatic breast cancer, and we will introduce the new category of HER2-low breast carcinomas.

Quantum Dots: Synthesis, Antibody Conjugation, and HER2-Receptor Targeting for Breast Cancer Therapy.

Breast cancer is becoming one of the main lethal carcinomas in the recent era, and its occurrence rate is increasing day by day. There are different breast cancer biomarkers, and their overexpression takes place in the metastasis of cancer cells. The most prevalent breast cancer biomarker is the human epidermal growth factor receptor2 (HER2). As this biomarker is overexpressed in malignant breast tissues, it has become the main focus in targeted therapies to fight breast cancer. There is a cascade of mechanisms involved in metastasis and cell proliferation in cancer cells. Nanotechnology has become extremely advanced in targeting and imaging cancerous cells. Quantum dots (QDs) are semiconductor NPs, and they are used for bioimaging, biolabeling, and biosensing. They are synthesized by different approaches such as top-down, bottom-up, and synthetic methods. Fully human monoclonal antibodies synthesized using transgenic mice having human immunoglobulin are used to target malignant cells. For the HER2 receptor, herceptin® (trastuzumab) is the most specific antibody (Ab), and it is conjugated with QDs by using different types of coupling mechanisms. This quantum dot monoclonal antibody (QD-mAb) conjugate is localized by injecting it into the blood vessel. After the injection, it goes through a series of steps to reach the intracellular space, and bioimaging of specifically the HER2 receptor occurs, where apoptosis of the cancer cells takes place either by the liberation of Ab or the free radicals.

Inhibition of Human Epidermal Growth Factor Receptor-2 (HER-2) from Pomelo (Citrus maxima) Flavonoid Compounds: an In Silico Approach

Citrus maxima or pomelo is a plant that has potential as an anticancer because it contains flavonoids. One of the targets of breast anticancer receptors is the HER-2 protein. This research aims to determine the anticancer activity, the toxicity of the compound, and the prediction of physicochemical properties of flavonoids contained in Citrus maxima through in silico approach. Flavonoid compounds were screened using SwissADME with Lipinski's rule of five, Torsion, TPSA, and P-Gp Non-Substrate. Compounds that passed the screening were carried out molecular docking to the HER-2 receptor (PDB ID: 3PP0) using the Molegro Virtual Docker (MVD). The HER-2 receptor (GDP ID: 3PP0) was declared valid because it had RMSD<2Å. The results showed that there were 11 flavonoid compounds that passed the screening and had a lower rerank score than the comparison compound Trastuzumab. Toxicity was predicted using the Protox II online tool and the results showed that the flavonoid compounds were in the safe limits, namely classes 5 and 3. Based on this research, it can be concluded that acacetin, diosmetin, honyucitrin, isosinensetin, nobiletin, sinensetin, and tangeretin can be candidates for breast cancer drugs based on natural ingredients.Keywords: breast cancer, Citrus maxima, HER-2, in silico.

Evaluation of the correlation between Ki-67 proliferative index and the histopathological grade of invasive neoplasms in early breast cancer aged < 70 years of age: a review of 300 cases

Background and objectives: according to the WHO 2018 reports, breast cancer is the fourth most common cause of cancer deaths worldwide. The breast cancer is recognized as the most common malignancy in the UK, it accounts for about 15% of all newly diagnosed malignancies, followed by prostate (13%), lung (13%), and bowel (11%). Ki-67 proliferative index became a key element in the diagnostic process of breast cancer, in addition to its role as a predictive tool and prognostic marker during the planning of adjuvant therapy as hormonal manipulation of systemic chemotherapy. The study aims to present the correlation analysis between Ki-67 and the different histological grade in breast cancer tumours. Material and methods: a cohort of 300 patients treated for early breast cancer was included in the study. The demographic data, histopathological subtype, hormonal and HER2 (Human epidermal growth factor receptor-2) receptor status and Ki-67 were analysed. The cut-off point was set at 20% to distinguish “high Ki-67” from “low Ki-67”. Results: about 35% (n = 106) of the cases were grade II with low Ki-67 , 26% (n = 79) grade III with high Ki-67, 19% (n = 56) grade II with high Ki-67, 11% (n = 34) grade I with low Ki-67. The high Ki-67 seen in 135 patients who belong to grade II and III groups (45%), where low Ki-67 in 42% of those cases, however, grade III alone contained more cases of high Ki-67 than any other histological grade group. Conclusions: a higher tumour histopathologic grade was correlated with higher Ki-67 values (OR = 7.12, 95% CI 16.75–3.03; p < 0.0001).

In-silico based identification of phytochemicals from Houttuynia cordata Thunb. as potential inhibitors for overexpressed HER2 and VEGFR2 cancer genes

Human epidermal growth factor receptor2 (HER2) and Vascular endothelial growth factor receptor2 (VEGFR2) – a tyrosine kinase receptors play a key role in breast and stomach cancers. The overexpression of HER2 and VEGFR2 genes increases the number of HER2 and VEGFR2 in the cell which initiates breast and stomach cancer respectively. The phytochemicals from traditional medicinal herb Houttuynia cordata Thunb. are reported to possess anti-inflammatory and anti-cancer potential. However, isolation of phytochemicals from this herb is fraught with uncertainly and time-consuming. Here, a molecular docking approach provides probable binding affinities between the receptors and phytochemicals (ligands) which initiate the first step of anticancer drug discovery and development. In the present study, In-silico docking approaches were used to identify the top-hit phytochemicals from H. cordata as potential inhibitors for overexpressed HER2 (breast) and VEGFR2 (stomach) cancer genes. A total of 100 biologically active phytochemicals from H. cordata were screened and docked against the ligand-binding pocket of HER2 and VEGFR2 kinase domains. Docking results revealed only a few phytochemicals (molecules) which appropriately fit into the ligand-binding pocket with higher binding affinity than the natural ATP ligand. A competitive docking was used to ascertain the top-hit phytochemicals that bind perfectly to the ATP ligand-binding pocket. Among the top-hit phytochemicals docked from H. cordata, the β-sitosterol and Quercetin showed highest binding affinity towards HER2 and VEGFR2 receptors using both hydrogen and hydrophobic interactions. This study confirmed β-sitosterol and Quercetin as potential drug candidates against breast and stomach cancer. Communicated by Ramaswamy H. Sarma

Abstract PD6-09: Herpet study- PET imaging of HER2 expression in breast cancer using the novel Affibody tracer [18F]GE-226, a first in patient study

Abstract Background 20% of breast cancers have over-expression of the human epidermal growth factor receptor-2 (HER2), which is an adverse prognostic factor and used to guide therapy selection. At present HER2 expression can only be determined using biopsy material which is then analysed using immunohistochemistry or fluorescence in situ hybridisation. GE-226 is a radiolabelled Affibody® tracer which binds to the HER2 receptor with high affinity at a different epitope than trastuzumab. Heterogeneous expression does exist but the impact this has on treatment response has not been well assessed. A non-invasive method for determining HER2 expression could have several advantages and help select appropriate therapy for patients. Trial DesignPatients with locally advanced or metastatic breast cancer were recruited and scanned for 65 mins after iv injection of 200MBq (mean activity injected for each patient 198 MBq (range 164-219MBq), mean radiochemical purity 94.6%) of tracer, with one dynamic bed position, and then a half-body scan was performed. Blood sampling was used to measure metabolism of the tracer. Safety was recorded. HER2-extracellular domain (ECD) domain was measured in blood. The original accrual target was 16 patients. Tumoural uptake was quantified by semi-quantitative and fully quantitative parameters in HER2 positive and HER2 negative tumours. ResultsThirteen patients were recruited. Scans were well tolerated. There were no serious adverse events. GE-226 was metabolised into a single metabolite in the liver. 96.8 % parent remained at 60 minutes post injection. There was a significant difference between HER2 positive and HER2 negative tumoural uptake of tracer as measured by SUVmean and SUVmax (p<0.05). Comparing HER2 positive to HER2 negative cases, there was also a significant difference between tumour to normal tissue uptake ratios (p<0.05). Heterogeneous uptake was observed in the same patient. Tumoural uptake increased over time. Uptake in salivary glands and the thyroid gland was noted. In one patient GE-226 was able to differentiate between lymphadenopathy due to sarcoidosis and cancer and was superior to FDG which had shown widespread uptake in the same patient. Conclusions[18F]GE-226 imaging is well tolerated and shows promise for imaging of HER2 positive breast cancer. Further studies with this agent are now planned. Citation Format: Laura M. Kenny, Gosala S. Gopalakrishnan, Tara D. Barwick, Vijay Vaja, S. Hope McDevitt, Robert Punjani, Neva H. Patel, Rathi Ramakrishnan, Naina R. Patel, Stephen Johnston, Janine Mansi, Gary J. Cook, Fiona J. Gilbert, Franklin I. Aigbirhio, Duncan Hiscock, Eric O. Aboagye. Herpet study- PET imaging of HER2 expression in breast cancer using the novel Affibody tracer [18F]GE-226, a first in patient study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-09.

Correlation of expression of hormone and HER2 receptors with various clinico-pathological prognostic parameters and with each other in malignant breast lesion

BackgroundEstrogen receptors (ER), progesterone receptors (PR) and the human epidermal growth factor receptor-2 (HER2) are basic breast cancer molecular markers that are also best recognized prognostic factors and predictors of type of targeted therapy to be given. The objectives are to study the correlation of expression of hormone and HER2receptors with various clinico-pathological prognostic parameters like patient's age at diagnosis, menopausal status, tumor size, histological grade and lymph node status of tumor and with each other in malignant breast lesion. MethodsFor this study histopathology (HP) and immunohistochemistry (IHC) slides of excised specimens of 330 female patients with a palpable breast lump deposited to the pathology department of a hospital as a part of routine diagnostic procedure, were evaluated under the guidance of trained doctors who have minimum 5 years of experience in oncopathology. The author has no direct involvement with patients, informed consent was not necessary and data were collected after getting permission from concerned authority. ResultsThis study finds significant relationship between hormone receptors and all clinico-pathological prognostic parameters taken for comparison except age at diagnosis. HER2 status has significant relationship with all clinico-pathological prognostic parameters; hormone and HER2 status suggests an inverse relationship. ConclusionsMien of hormone receptors expression in breast cancer is related with better prognostic factors such as older age, postmenopausal status, smaller tumor size, low histological grade and negative lymph node status, however the opposite is correct for HER2. Hormone receptors and HER2 have an inversely proportionate relationship with each other.

Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody.

Amplification and overexpression of HER2 (human epidermal growth factor receptor 2), an ErbB2 receptor tyrosine kinase, have been implicated in human cancer and metastasis. A bispecific tetravalent anti-HER2 antibody (anti-HER2-Bs), targeting two non-overlapping epitopes on HER2 in domain IV (trastuzumab) and domain II (39S), has been reported to induce rapid internalization and efficient degradation of HER2 receptors. In this study, we investigated the molecular mechanism of this antibody-induced rapid HER2 internalization and intracellular trafficking. Using quantitative fluorescent imaging, we compared the internalization kinetics of anti-HER2-Bs and its parental arm antibodies, alone or in combinations and under various internalization-promoting conditions. The results demonstrated that concurrent engagement of both epitopes was necessary for rapid anti-HER2-Bs internalization. Cellular uptake of anti-HER2-Bs and parental arm antibodies occurred via clathrin-dependent endocytosis; however, inside the cells antibodies directed different trafficking pathways. Trastuzumab dissociated from HER2 in 2 h, enabling the receptor to recycle, whereas anti-HER2-Bs stayed associated with the receptor throughout the entire endocytic pathway, promoting receptor ubiquitination, trafficking to the lysosomes, and efficient degradation. Consistent with routing HER2 to degradation, anti-HER2-Bs significantly reduced HER2 shedding and altered its exosomal export. Collectively, these results enable a better understanding of the mechanism of action of anti-Her2-Bs and can guide the rational design of anti-HER2 therapeutics as well as other bispecific molecules.

A study of human epidermal growth factor receptor-2 (HER-2) in carcinoma esophagus (Single Institutional Tertiary Cancer Centre study from Northeast part of India)

Objectives: Esophageal cancer both squamous cell (SCC) and adenocarcinoma have poor outcomes with high morbidity and mortality. Our hospital-based registry for the year 2017–2018 showed that esophageal cancer constituted 22.7% of the annual caseload. The main objective of this study was to determine the presence of HER-2 receptors in patients with esophageal carcinoma in our region. Material and Methods: From September 2018 to September 2019, data regarding the expression of HER-2 receptors was analyzed in 133 patients of esophageal carcinoma. Data were statistically described as frequencies (number of cases) and percentages where appropriate. Chi-square and Fischer’s exact test was used to find out the association between categorical variables. A P < 0.05 was considered as statistical significant at 95% confidence interval. The statistical analysis was performed using SSPS software version 17.0. Results: A total of 133 patients were taken into study. The majority of patients were males (96) with a mean age of 52 years. Squamous cell carcinoma was predominant histology. HER-2 receptor positivity was seen in 6.01% of patients. Patients with HER-2 receptor positivity presented in advanced stage with poor functional status and poor grades of differentiation. Statistically significant correlation of Her-2 expression was seen with stage (P = 0.001) and pathology of tumor (P = 0.0001). Conclusion: Squamous cell carcinoma of esophagus still predominates in Northeast part of India. For studying the role of effective targeted therapies, knowledge of frequency of HER-2 receptor positivity is of utmost importance in our population and our study aims to answer this question. The present study shows a low prevalence of HER-2 neu overexpression in our community, probably due to the disproportionately high incidence of SCC compared to adenocarcinoma. Patients with HER-2 receptor positivity presented in advanced stage with poor functional status and poor grades of differentiation.

Modulation of Estrogen α and Progesterone Receptors in Triple Negative Breast Cancer Cell Lines: The Effects of Vorinostat and Indole-3-Carbinol In Vitro.

Triple negative cancer (TNBC) is a subtype of breast cancer that is highly aggressive, with poor prognosis and responds differently to treatments. This study investigated the role of vorinostat and indole-3-carbinol (I3C) on regulating critical receptors that are not normally expressed in TNBC. Using real-time PCR, immunostaining, and western blots, the re-expression of estrogen receptor α (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) receptors was examined in four different TNBC cell types. ERα was re-expressed in three subtypes using vorinostat and I3C. Re-expression of the PR by vorinostat was also detected. Neither vorinostat nor I3C resulted in re-expression of the HER2 receptor. A significant decrease in growth and sensitivity to tamoxifen was also noted. The results of this study show that vorinostat and I3C modulate the re-expression of critical receptors in certain subtypes of TNBC through several pathways and these effects can be influenced by the molecular profiles of TNBCs.

Discordance of immunohistochemical markers between primary and recurrent or metastatic breast cancer: A retrospective analysis of 107 cases.

There is a discordance in the immunohistochemical markers between primary breast cancer and recurrent or metastatic breast cancer. This study aimed to assess the recent trends and prognostic features in the treatment of recurrent or metastatic breast cancerOverall, 107 patients were identified from January 2001 to August 2018 at the Peking Union Medical College Hospital, Beijing, and People's Republic of China to obtain a cohort of breast carcinoma patients who were confirmed to have recurrent or metastatic breast cancer by histopathology. We evaluated patient and tumor characteristics and examined the relationships between these factors and prognosis.The estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) positivity, and Ki67 index in primary breast cancer were 63.6% (68/107), 58.9% (63/107), 19.8% (21/106) and 75.8% (75/99), respectively, while those in recurrent or metastatic lesions were 60.6% (65/107) (P = .672), 46.7% (50/107) (P = 0.013), 23.8% (25/105) (P = 0.482)and 83.5%(81/97)(P = 0.178), respectively. The discordance rate of HER2 expression was 10.6% (11/104), while that of PR expression was 23.3% (21/90). HER2 was the most stable biomarker. The discordance rates for luminal A and HER2 were as high as 100% and 25%, respectively, while the luminal B and triple negative values were as low as 8.3% and 5.3%, respectively.ER and PR positivity and the Ki-67 index tended to increase due to recurrence or metastases; however, the discordance for PR and Ki-67 was high. PR is more variable than ER in the expression of primary and recurrent or metastatic breast cancer. The expression of HER2 receptor was the most stable and the discordance rate of triple negative breast cancer was the lowest. Therefore, although changes in biomarkers are due to recurrence or metastasis, pathological confirmation and exploration of markers are very important.

Role of Melatonin in Breast Carcinoma: Correlation of Expression Patterns of Melatonin-1 Receptor With Estrogen, Progesterone, and HER2 Receptors.

Breast carcinoma is a multifaceted-etiology malignancy. The presence of estrogen (ER), progesterone (PR), and HER2 (human epidermal growth factor receptor 2) receptors in breast carcinoma tissue has therapeutic implications. Recent studies indicate that pineal hormone melatonin by its receptor melatonin 1 (MT1) also influences the development and growth of breast cancer cells. The aim of this cross-sectional study was to elucidate the expression pattern of MT1 receptor in relation to estrogen, progesterone, and HER2 receptors in breast carcinoma. Two groups (receptor positive and triple negative) of breast carcinoma were taken. For comparison, normal mammary tissue was used as control. Immunohistochemistry was carried out using anti-melatonin receptor 1A antibody. Membranous/cytoplasmic expression was seen more than the nuclear expression in the cancerous tissue. Positive correlation of the MT1 expression was seen with ER, PR, and HER 2 receptor. Higher MT1 receptor expression was seen in the receptor-positive cases in comparison with triple-negative cases, which might signify melatonin deficiency in the former, leading to reactive increase in cell receptors. No correlation of MT1 expression with Ki67 index or lymph node status in both receptor-positive and triple-negative cases was found. Normal mammary tissue mainly showed cytoplasmic MT1 immunoreactivity of epithelial cells (ducts and acini), myoepithelial cells, and lining epithelium of blood vessels. Receptor-positive cases would, therefore, benefit from the use of melatonin as supporting therapy. This indicates that melatonin receptor status can be used as an independent pathologic indicator to evaluate breast carcinoma tissue, and melatonin receptor status may help to determine treatment protocols.