Gene Summary

Gene:NEURL1; neuralized E3 ubiquitin protein ligase 1
Aliases: neu, NEUR1, NEURL, RNF67, neu-1, bA416N2.1
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase NEURL1
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (11)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Chromosome 10
  • Proportional Hazards Models
  • High-Throughput Nucleotide Sequencing
  • Immunoenzyme Techniques
  • Calcium-Binding Proteins
  • Phenotype
  • Signal Transduction
  • Brain Tumours
  • Childhood Cancer
  • Down-Regulation
  • Jagged-1 Protein
  • neurofilament protein H
  • Adolescents
  • Non-Fibrillar Collagens
  • Basic Helix-Loop-Helix Transcription Factors
  • Homeodomain Proteins
  • Infant
  • Oligonucleotide Array Sequence Analysis
  • HES1 protein, human
  • Drosophila Proteins
  • Promoter Regions
  • Cell Cycle Proteins
  • Medulloblastoma
  • JAG1 protein, human
  • Autoantigens
  • collagen type XVII
  • DNA Methylation
  • Kidney Cancer
  • Renal Cell Carcinoma
  • Notch Receptors
  • Intercellular Signaling Peptides and Proteins
  • Ubiquitin-Protein Ligases
  • Membrane Proteins
  • Epigenetics
  • Cerebellum
  • HEY1 protein, human
  • Cerebellar Neoplasms
  • Western Blotting
  • Esophageal Cancer
  • Disease-Free Survival
  • Messenger RNA
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: NEURL1 (cancer-related)

Qamar S, Khokhar MA, Farooq S, et al.
Association of p53 Overexpression with Hormone Receptor Status and Triple Negative Breast Carcinoma.
J Coll Physicians Surg Pak. 2019; 29(2):164-167 [PubMed] Related Publications
OBJECTIVE: To determine association of p53 overexpression with hormone receptor status in breast carcinoma.
STUDY DESIGN: Descriptive cross-sectional study.
PLACE AND DURATION OF STUDY: Department of Pathology in collaboration with Department of Oncology, King Edward Medical University, Lahore, from January 2017 to January 2018.
METHODOLOGY: All adult female patients coming to Department of Oncology with reports of breast cancer biopsy and receptor status were included. Their age, type of surgery, grade of cancer, stage of cancer, and hormone receptor status were noted from records. P53 immunomarker was applied on tumor containing tissue blocks. Pearson Chi-square test was run for strength of association between the variables using SPSS V. 22.
RESULTS: Mean age of 91 patients at diagnosis was 48 years ±12.49. Fifty-five (60.4%) patients had ER positive tumors, 36 (39.6%) were ER negative, 53 (58.2%) had PR positive status, and 38 (41.8%) were negative. Same number was seen in HER2 neu staining. Out of 91 cases, 31 (34.1%) were p53 positive and 60 (65.9%) were negative. Out of 55 (60.4%) ER positive cases, 11 (12.1%) were positive for p53 and 44 (48.4%) were p53 negative (p<0.001). PR positive cases (53/58.2%) showed p53 positivity in 7 (7.7%) and negativity in 46 (50.5%) cases (p< 0.001). HER2 positive cases were positive for p53 stain in 8 (8.8%) and negative in 45 (49.5%) cases (p<0.001). Fifteen (16.48%) biopsies were negative for all three hormone receptors. P53 was positive in all of these hormone receptor negative tumors (15/15, 100%), although 9 (60%) showed strong positivity and 6 (40%) exhibited weak staining intensity of p53.
CONCLUSION: P53 overexpression is less frequent in hormone receptor positive breast cancers. However, hormone receptor negative (triple negative) tumors overwhelmingly overexpress p53 protein in tumor cells. P53, detected either immunohistochemically or serologically, can serve to predict poor prognosis and survival in breast cancer patients, unless newer anti-p53 treatments are introduced in Pakistan.

Gunaratna RT, Santos A, Luo L, et al.
Dynamic role of the codon 72 p53 single-nucleotide polymorphism in mammary tumorigenesis in a humanized mouse model.
Oncogene. 2019; 38(18):3535-3550 [PubMed] Related Publications
Female breast cancer (BrCa) is the most common noncutaneous cancer among women in the United States. Human epidemiological studies reveal that a p53 single-nucleotide polymorphism (SNP) at codon 72, encoding proline (P72) or arginine (R72), is associated with differential risk of several cancers, including BrCa. However, the molecular mechanisms by which these variants affect mammary tumorigenesis remain unresolved. To investigate the effects of this polymorphism on susceptibility to mammary cancer, we used a humanized p53 mouse model, homozygous for either P72 or R72. Our studies revealed that R72 mice had a significantly higher mammary tumor incidence and reduced latency in both DMBA-induced and MMTV-Erbb2/Neu mouse mammary tumor models compared to P72 mice. Analyses showed that susceptible mammary glands from E-R72 (R72 x MMTV-Erbb2/Neu) mice developed a senescence-associated secretory phenotype (SASP) with influx of proinflammatory macrophages, ultimately resulting in chronic, protumorigenic inflammation. Mammary tumors arising in E-R72 mice also had an increased influx of tumor-associated macrophages, contributing to angiogenesis and elevated tumor growth rates. These results demonstrate that the p53 R72 variant increased susceptibility to mammary tumorigenesis through chronic inflammation.

Priyadarshini R, Raj GM, Kayal S, et al.
Influence of ABCB1 C3435T and C1236T gene polymorphisms on tumour response to docetaxel-based neo-adjuvant chemotherapy in locally advanced breast cancer patients of South India.
J Clin Pharm Ther. 2019; 44(2):188-196 [PubMed] Related Publications
WHAT IS KNOWN AND OBJECTIVE: Variable response to docetaxel-based neo-adjuvant chemotherapy (NACT) in breast cancer patients had been reported. Genetic polymorphisms in the ABCB1 gene coding for the efflux transporter MDR1 (P-glycoprotein, P-gp) could result in altered tumour response. Hence, this study was proposed to assess the effect of single nucleotide polymorphisms (SNPs) of ABCB1 gene on tumour response in locally advanced breast cancer patients (LABC) of South India who have a distinct genetic makeup.
METHODS: Out of 162 LABC patients recruited, 129 patients were included for the final analysis. DNA was extracted by "phenol-chloroform extraction method" from the WBCs, and genotyping for SNPs rs1045642 (C3435T) and rs1128503 (C1236T) in ABCB1 gene was performed with real-time PCR system using validated TaqMan
RESULTS AND DISCUSSION: A total of 102 (79.1%) patients were found to be responders and 27 (20.9%) patients were found to be non-responders to docetaxel therapy. Patients with "CT/TT" genotypes (response rate: 83.3%) of ABCB1 (C1236T) gene showed better tumour response than those with "CC" genotype (response rate: 16.6%) [OR = 2.94 (CI: 1.15-7.52); P = 0.03]. However, on performing binary logistic regression, neither the studied SNPs nor the non-genetic factors like age, BMI, postmenopausal status, laterality of the tumour, ER status, PR status and Her-2/neu status were found to be associated with tumour response to docetaxel (P > 0.05).
WHAT IS NEW AND CONCLUSION: The tumour response to docetaxel was significantly influenced by the SNP C1236T of ABCB1 gene coding for the P-gp. However, when adjusted for other non-genetic factors, neither of the ABCB1 variants were found to be associated with tumour response to docetaxel-based NACT in LABC patients of South India.

Bonazzoli E, Cocco E, Lopez S, et al.
PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers.
Gynecol Oncol. 2019; 153(1):158-164 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
OBJECTIVE: Aberrant expression of HER2/neu and PIK3CA gene products secondary to amplification/mutations are common in high-grade-serous-endometrial (USC) and ovarian-cancers (HGSOC). Because scant information is currently available in the literature on the potential negative effect of PIK3CA mutations on the activity of afatinib, in this study we evaluate for the first time the role of oncogenic PIK3CA mutations as a potential mechanism of resistance to afatinib in HGSOC and USC overexpressing HER2/neu.
METHODS: We used six whole-exome-sequenced primary HGSOC/USC cell-lines and three xenografts overexpressing HER2/neu and harboring mutated or wild-type PIK3CA/PIK3R1 genes to evaluate the role of PI3K-mutations as potential mechanism of resistance to afatinib, an FDA-approved pan-c-erb-inhibitor in clinical trials in USC. Primary-USC harboring wild-type-PIK3CA gene was transfected with plasmids encoding oncogenic PIK3CA-mutations (H1047R/E545K). The effect of afatinib on HER2/PI3K/AKT/mTOR pathway was evaluated by immunoblotting.
RESULTS: We found PI3K wild-type cell-lines to be significantly more sensitive (lower IC
CONCLUSIONS: Oncogenic PI3K mutations may represent a major mechanism of resistance to afatinib. Combinations of c-erb with PIK3CA, AKT or mTOR inhibitors may be necessary to more efficiently block the PIK3CA/AKT/mTOR pathway.

Plum PS, Gebauer F, Krämer M, et al.
HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma.
BMC Cancer. 2019; 19(1):38 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact.
METHODS: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data.
RESULTS: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041).
CONCLUSION: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.

Tanioka M, Mott KR, Hollern DP, et al.
Identification of Jun loss promotes resistance to histone deacetylase inhibitor entinostat through Myc signaling in luminal breast cancer.
Genome Med. 2018; 10(1):86 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Based on promising phase II data, the histone deacetylase inhibitor entinostat is in phase III trials for patients with metastatic estrogen receptor-positive breast cancer. Predictors of sensitivity and resistance, however, remain unknown.
METHODS: A total of eight cell lines and nine mouse models of breast cancer were treated with entinostat. Luminal cell lines were treated with or without entinostat at their IC
RESULTS: Luminal models displayed enhanced sensitivity to entinostat as compared to basal-like or claudin-low models. Both in vitro and in vivo luminal models showed significant downregulation of Myc gene signatures following entinostat treatment. Myc gene signatures became upregulated on tumor progression in vivo and overexpression of Myc conferred resistance to entinostat in vitro. Further examination of resistance mechanisms in MMTV/Neu tumors identified a portion of mouse chromosome 4 that had DNA copy number loss and low gene expression. Within this region, Jun was computationally identified to be a driver gene of resistance. Jun knockdown in cell lines resulted in upregulation of Myc signatures and made these lines more resistant to entinostat. Jun-deleted samples, found in 17-23% of luminal patients, had significantly higher Myc signature scores that predicted worse survival.
CONCLUSIONS: Entinostat inhibited luminal breast cancer through Myc signaling, which was upregulated by Jun DNA loss to promote resistance to entinostat in our models. Jun DNA copy number loss, and/or high MYC signatures, might represent biomarkers for entinostat responsiveness in luminal breast cancer.

Alshareeda AT, Rakha E, Alghwainem A, et al.
The effect of human placental chorionic villi derived mesenchymal stem cell on triple-negative breast cancer hallmarks.
PLoS One. 2018; 13(11):e0207593 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Mesenchymal stem cells (MSCs) can influence the tumour microenvironment (TEM) and play a major role in tumourigenesis. Triple-negative [Ostrogen receptor (ER-), Progesterone receptor (PgR-), and HER2/neu receptor (HER2-)] breast cancer (TNBC) is an aggressive class of BC characterized by poor prognosis and lacks the benefit of routinely available targeted therapies. This study aims to investigate the effect of human placental chorionic villi derived MSCs (CVMSCs) on the behavior of TNBC in vitro. This was done by assaying different cancer hallmarks including proliferation, migration and angiogenesis. Cell proliferation rate of TNBC cell line (MDA-MB231) was monitored in real time using the xCELLigence system. Whereas, Boyden chamber migration assay was used to measure MDA-MB231 motility and invasiveness toward CVMSCs. Finally, a three-dimensional (3D) model using a co-culture system of CVMSCs with MDA-MB231 with or without the addition of human umbilical vein endothelial cells (HUVECs) was created to assess tumour angiogenesis in vitro. CVMSCs were able to significantly reduce the proliferative and migratory capacity of MDA-MB231 cells. Co-culturing of MDA-MB231 with CVMSCs, not only inhibited the tube formation ability of HUVECs but also reduced the expression of the BC characteristic cytokines; IL-10, IL-12, CXCL9 and CXCL10 of CVMSCs. These results support the hypothesis that CVMSCs can influence the behavior of TNBC cells and provides a basic for a potential therapeutic approach in a pre-clinical settings. The data from this study also highlight the complexity of the in vitro cancer angiogenesis model settings and regulations.

Dorokhov YL, Sheshukova EV, Bialik TE, Komarova TV
Human Endogenous Formaldehyde as an Anticancer Metabolite: Its Oxidation Downregulation May Be a Means of Improving Therapy.
Bioessays. 2018; 40(12):e1800136 [PubMed] Related Publications
Malignant cells are characterized by an increased content of endogenous formaldehyde formed as a by-product of biosynthetic processes. Accumulation of formaldehyde in cancer cells is combined with activation of the processes of cellular formaldehyde clearance. These mechanisms include increased ALDH and suppressed ADH5/FDH activity, which oncologists consider poor and favorable prognostic markers, respectively. Here, the sources and regulation of formaldehyde metabolism in cancer cells are reviewed. The authors also analyze the participation of oncoproteins such as fibulins, FGFR1, HER2/neu, FBI-1, and MUC1-C in the control of genes related to formaldehyde metabolism, suggesting the existence of two mutually exclusive processes in cancer cells: 1) production and 2) oxidation and elimination of formaldehyde from the cell. The authors hypothesize that the study of the anticancer properties of disulfiram and alpha lipoic acid - which affect the balance of formaldehyde in the body - may serve as the basis of future anticancer therapy.

Kılıçarslan A, Dogan HT, Süngü N, et al.
Association between Her2/neu status in colorectal carcinoma and clinicopathological features: a retrospective study using whole - tissue sections.
Pol J Pathol. 2018; 69(2):143-149 [PubMed] Related Publications
The human epidermal growth factor receptor 2 (Her2/neu) signal pathway plays a significant role in the occurance of various solid tumor types. The rate of Her2/neu in colorectal carcinoma (CRC) is not clearly elucidated. In this study, we discuss the association between Her2/neu overexpression and clinicopathological parameters in CRC. Her2/neu immunohistochemical (IHC) staining was performed on whole sections of formalin fixed paraffin embedded tumor tissues of 100 CRC resections. Cases with score 3+ and score 2+ expressions were further evaluated by silver in-situ hybridization (ISH) for the existence of Her2/neu gene amplification. Her2/neu membranous overexpression was observed in 12 of the 100 cases (6 cases with a score 3+ and 6 cases with a score 2+) and 6 of these were heterogenous. There were 10 cases with Her2/neu amplification (6/6 score 3+, 4/6 score 2+). Strong cytoplasmic staining was observed in 5 cases. Membranous scores were either 3+ or 2+ in 3 of these 5 cases. Moreover, there was Her2/neu amplification in 2 of these 3 cases. Her2/neu amplification status and overexpression was not related to clinicopathological parameters and overall survival. More clear results can be obtained from studies with Her2/neu IHC and ISH test on whole sections.

Zadvornyi TV, Lukianova NY, Borikun TV, Chekhun VF
Effects of exogenous lactoferrin on phenotypic profile and invasiveness of human prostate cancer cells (DU145 and LNCaP) in vitro.
Exp Oncol. 2018; 40(3):184-189 [PubMed] Related Publications
AIM: To investigate the biological effects of exogenous lactoferrin (LF) on phenotypic profile and invasiveness of human prostate cancer (PC) cells in vitro.
MATERIALS AND METHODS: Human PC cell lines (LNCaP, DU-145) were cultured with an exogenous LF at a dose corresponding to IC30. The expression levels of steroid hormone receptors (androgen receptor, estrogen receptor, progesterone receptor), Her2/neu, Ki-67, E- and N-cadherin, were monitored by immunohistochemical analysis. The levels of miRNAs were assessed using q-PCR. The invasive activity of the cells was examined in a standard invasion test.
RESULTS: Exogenous LF reduced expression of steroid hormone receptors (ERα and PR) and Ki-67 in both PC cell lines. The expression of E-cadherin increased significantly in LF-treated DU-145 cells. Also, we established the decrease in invasive activity upon LF treatment by 40% and 30% in DU-145 and LNCaP cells, respectively. In DU-145 cells, incubation with exogenous LF resulted in an increase in the expression of oncosuppressive (miR-133a and miR-200b) miRNAs.
CONCLUSIONS: Exogenous LF causes the changes in phenotypic characteristics of PC cells and levels of oncogenic and oncosuppressive miRNAs involved in the regulation of key cellular processes.

Menderes G, Lopez S, Han C, et al.
Mechanisms of resistance to HER2-targeted therapies in HER2-amplified uterine serous carcinoma, and strategies to overcome it.
Discov Med. 2018; 26(141):39-50 [PubMed] Related Publications
Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that accounts for up to 40% of all endometrial cancer-related deaths. Recent whole-exome sequencing studies have revealed HER2/neu amplification in 27-44% of USC patients, supporting HER2 as an attractive pathway for target therapies based on monoclonal antibodies or tyrosine kinase inhibitors. Preclinical studies and a recently published prospective randomized trial with trastuzumab in combination with chemotherapy demonstrated promising results with anti-HER2-targeted therapies in advanced and recurrent USC patients. In contrast, single-agent trastuzumab or tyrosine kinase inhibitors (i.e., lapatinib) were unable to demonstrate significant clinical activity and/or durable tumor growth inhibition. Combinatorial therapies may represent novel, highly effective therapeutic strategies to overcome inborn or acquired resistance to HER2/neu-targeted therapies in HER2-amplified USC patients. This study presents a comprehensive review of the mechanisms of USC resistance to HER2-targeted therapies and potential strategies to overcome it.

Valentini AM, Cavalcanti E, Di Maggio M, Caruso ML
RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine.
Appl Immunohistochem Mol Morphol. 2018; 26(8):539-544 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Cetuximab and panitumumab monoclonal antibodies are a milestone in the history of treatment of metastatic colorectal cancer (mCRC) and point toward future directions for personalized treatment. Recent studies have shown that broader RAS testing is needed to select patients for targeted therapy. The objectives of our study were to identify the prevalence of RAS mutations and evaluate human epidermal growth factor receptor 2 (HER2) expression in KRAS exon 2 wild-type (WT) mCRC patients, correlating the findings with objective response rate, progression-free survival, and overall survival. In total, 29 mCRC patients undergoing treatment with cetuximab therapy were enrolled in this study. By pyrosequencing, mutations were found in 17% of nonresponder patients, in KRAS codon 146 and NRAS codon 12. HER2 positivity was limited to only 1 responder carcinoma specimen. There was no correlation between RAS mutation, HER2/neu expression, and clinicopathologic findings. We highlighted significantly the differences between objective response rate and RAS gene status. The overall survival and progression-free survival of RAS WT patients were higher compared with those with RAS-mutated disease. Clinical response to cetuximab therapy is impaired in the presence of RAS-expanded mutations. In fact, our finding of 5 mutations in RAS-expanded genes allowed us to understand the resistance to cetuximab in 33% of KRAS WT exon 2 nonresponder patients. HER2 does not seem to be a potential biomarker for cetuximab-targeted therapy. These analyses suggest that the assessment of other biomarkers is needed to determine the best treatment for patients with mCRC, to maximize benefit and minimize harm.

Völker HU, Weigel M, Strehl A, Frey L
Levels of uPA and PAI-1 in breast cancer and its correlation to Ki67-index and results of a 21-multigene-array.
Diagn Pathol. 2018; 13(1):67 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
BACKGROUND: Conventional parameters including Ki67, hormone receptor and Her2/neu status are used for risk stratification for breast cancer. The serine protease urokinase plasminogen activator (uPA) and the plasminogen activator inhibitor type-1 (PAI-1) play an important role in tumour invasion and metastasis. Increased concentrations in tumour tissue are associated with more aggressive potential of the disease. Multigene tests provide detailed insights into tumour biology by simultaneously testing several prognostically relevant genes. With OncotypeDX®, a panel of 21 genes is tested by means of quantitative real-time polymerase chain reaction. The purpose of this pilot study was to analyse whether a combination of Ki67 and uPA/PAI-1 supplies indications of the result of the multigene test.
METHODS: The results of Ki67, uPA/PAI-1 and OncotypeDX® were analysed in 25 breast carcinomas (luminal type, pT1/2, max pN1a, G2). A statistical and descriptive analysis was performed.
RESULTS: With a proliferation index Ki67 of < 14%, the recurrence score (RS) from the multigene test was on average in the low risk range, with an intermediate RS usually resulting if Ki67 was > 14%. Not elevated values of uPA and PAI-1 showed a lower rate of proliferation (average 8.5%) than carcinomas with an increase of uPA and/or PAI-1 (average 13.9%); p = 0.054, Student's t-test. When Ki67 was > 14% and uPA and/or PAI-1 was raised, an intermediate RS resulted. These differences were significant when compared to cases with Ki67 < 14% with non-raised uPA/PAI-1 (p < 0.03, Student's t-test). Without taking into account the proliferative activity, an intermediate RS was also verifiable if both uPA and PAI-1 showed raised values.
CONCLUSION: A combination of the values Ki67 and uPA/PAI-1 tended to depict the RS to be expected. From this it can be deduced that an appropriate analysis of this parameter combination may be undertaken before the multigene test in routine clinical practice. The increasing cost pressure makes it necessary to base the implementation of a multigene test on ancillary variables and to potentially leave it out if not required in the event of a certain constellation of results (Ki67 raised, uPA and PAI-1 raised).

Lateef F, Jamal S, Nasir S
Her-2/neu Oncogene Amplification by Fluorescence In Situ Hybridization and Protein Overexpression on Immunohistochemistry in Breast Cancer.
J Coll Physicians Surg Pak. 2018; 28(8):581-585 [PubMed] Related Publications
OBJECTIVE: To investigate the concordance and discordance between the test results of Her-2/neu by immunohisto-chemistry (IHC) and flourescence In Situ hybridization (FISH) in breast cancer cases.
STUDY DESIGN: Descriptive cross-sectional study.
PLACE AND DURATION OF STUDY: Department of Histopathology, Dr. Ziauddin Hospital, Karachi, from 2011 to 2016.
METHODOLOGY: Forty-three specimens of invasive ductal carcinoma of breast were evaluated for grade and Her-2/neu status using IHC and FISH methods. Concordance and discordance between their results was determined.
RESULTS: There is 100% concordance between FISH and IHC in cases scoring 0, 1+ (negative) and 3+ (positive) immunostaining. Tumour cases scoring 2+ immunostaining showed amplification in 69.2% cases. All grade-I tumours were non-amplified on FISH, while most of the grade-III tumours showed Her-2/neu amplification on FISH. There is significant association of Her-2/neu IHC with tumour grade and FISH (p<0.05). A fairly high proportion i.e. 69.7% of cases showed Her-2/neu gene amplification. There was high concordance between Her-2/neu testing on IHC and FISH, (Kappa co-efficient 0.466, p <0.001).
CONCLUSION: Her-2/neu amplification increases with increasing grade of breast cancer. A high proportion of Her-2/neu gene amplified cases indicates aggressive disease in that area and need for FISH testing on large scale, which is the gold standard for equivocal cases on immunohistochemistry.

Sadaf, Habib M, Khan MA, et al.
Hypermethylated LATS2 gene with decreased expression in female breast cancer: A case control study from North India.
Gene. 2018; 676:156-163 [PubMed] Related Publications
BACKGROUND: LATS2, a presumed tumor suppressor gene located on chromosome 13q11-12 is involved in cell growth related activity like regulation of cell cycle at G1/S. The reduced expression of LATS2 has been reported in many tumors; including tumors of Breast, which is to the best of our knowledge has not been studied in north Indian female breast cancer population.
OBJECTIVE: Here, we looked upon the expression pattern and methylation status of the LATS2 gene in north Indian female breast cancer cases to further strengthen its role as a tumor suppressor gene and more importantly as a cancer biomarker.
METHODS: mRNA expression level was determined by real time PCR in 140 Breast cancer patients, Protein expression was studied by Immunohistochemistry and Promoter methylation was studied by Methylation specific PCR. All findings were correlated with clinicopathological features.
RESULTS: LATS2 mRNA expression was remarkably downregulated in 67.85% (95/140) cases. The expression of Large Associated Tumor Suppressor 2 at protein level was also absent in 67.85% (95/140) cases. The absence of LATS2 protein strongly correlated with promoter hypermethylation where 91 out of a total of 107 hyper methylated cases showed absence of protein (91/107, 85%). The absence of LATS2 protein was strongly significant with HER2 neu status (0.01), TNM staging (0.009) and Molecular subtype (0.024).
CONCLUSION: The decreased expression in breast cancer seems to be associated with hypermethylation of LATS2 promoter regions. Further LATS2 as a tumor suppressor can be recognized as a promising Biomarker in Breast cancer pathogenesis. Though, further studies, targeting larger sets of breast cancer population are required to establish LATS2 as a promising biomarker.

Akoz G, Diniz G, Ekmekci S, et al.
Evaluation of human epididymal secretory protein 4 expression according to the molecular subtypes (luminal A, luminal B, human epidermal growth factor receptor 2-positive, triple-negative) of breast cancer.
Indian J Pathol Microbiol. 2018 Jul-Sep; 61(3):323-329 [PubMed] Related Publications
Background/Aims: Human epididymal secretory protein 4 (HE4) is originally described as an epididymis-specific protein but more recently suggested to be a putative serum tumor marker for some tumors, including breast carcinomas. In this study, we aimed to investigate the interactions between HE4 expression and molecular subtypes of breast carcinomas.
Methods: HE4 expressions were studied in 242 formalin-fixed, paraffin-embedded breast carcinoma specimens and their association with different pathological and clinical parameters was evaluated.
Results: Immunohistochemical (IHC) staining for HE4 was negative in 3 (1.2%) cases, weakly positive (1+) in 7 (2.9%) cases, moderately positive (2+) in 58 (24.0%) cases, and strongly positive (3+) in 174 (71.9%) cases. A correlation between IHC HE4 staining grade and molecular groups was detected (P = 0.005). Furthermore, it was found that HE4 expression was strongly associated with histological tumor grade, c-erbB2 expression, and positive fluorescence in situ hybridization test results that detect human epidermal growth factor receptor 2 (HER2)/neu amplification (P = 0.022, P = 0.014, and P = 0.011).
Conclusion: This study showed that HE4 expression is associated with HER2/neu amplification in breast cancers. These results may be commented as HE4 expression rises in patients with HER2/neu amplification. As is known, HER2/neu amplification is a poor diagnostic factor in breast cancer and HE4 expression is possibly associated with poor prognosis.

Limoni SK, Moghadam MF, Moazzeni SM, et al.
Engineered Exosomes for Targeted Transfer of siRNA to HER2 Positive Breast Cancer Cells.
Appl Biochem Biotechnol. 2019; 187(1):352-364 [PubMed] Related Publications
Exosomes are the best options for gene targeting, because of their natural, nontoxic, non-immunogenic, biodegradable, and targetable properties. By engineering exosome-producing cells, ligands can be expressed fusing with exosomal surface proteins for targeting cancer cell receptors. In the present study, HER2-positive breast cancer cells were targeted with a modified exosome producing engineered HEK293T cell. For this purpose, the HEK293T cells were transduced by a lentiviral vector bearing-LAMP2b-DARPin G3 chimeric gene. Stable cells expressing the fusion protein were selected, and the exosomes produced by these cells were isolated from the culture medium, characterized, and then loaded with siRNA for subsequent delivery to the SKBR3 cells. Our results showed that stable HEK293T cells produced DARPin G3 on the surface of exosomes. These exosomes can bind specifically to HER2/Neu and are capable of delivering siRNA molecules against TPD52 gene into SKBR3 cell line down-regulating the gene expression up to 70%. Present approach is envisaged to facilitate genes and drugs transfer to HER2 cancer cells providing additional option for gene therapy and drug delivery.

Kryzhanivska AE, Dyakiv IB, Kyshakevych I
Clinical and immunohistochemical features of primary breast cancer and metachronous ovarian and endometrial tumors.
Exp Oncol. 2018; 40(2):124-127 [PubMed] Related Publications
The aim of the study was to assess the patterns of development of metachronous cancer (endometrial cancer, EC, and ovarian cancer, OC) in breast cancer (BC) patients dependent of receptor phenotype of breast tumors.
MATERIALS AND METHODS: In the study, 63 patients with ВС, who developed metachronous EC (n = 47) or OC (n = 16) were enrolled. Expression of estrogen receptor (ER), progesterone receptor (PR), HER/2neu was assessed using immunohistochemical approach.
RESULTS: BC in patients with metachronous EC and OC was characterized by a different frequency of molecular subtypes with the dominance of luminal A (36%) and B (43%) subtypes. In primary BC, we have established a correlation between ER expression and regional lymph nodes status (r = -0.50, p < 0.05); negative correlation between HER2/neu expression and tumor stage (r = -0.48, p < 0.05); between the molecular subtype of BC and its size (r = -0.33, p <0.05), the molecular subtype of primary BC and metastases in regional lymph nodes (r = 0.27, p <0.05). In the patients with luminal subtype BC metachronous tumors developed with the highest frequency (OC - 50%, EC - 50%). After treatment of primary BC metachronous tumors developed at different period: EC (22.2%) - most often in 3-5 years, OC (11.0%) - after 10 years and more.
CONCLUSION: Our data evidence on the clinical significance of the individual characteristics of the BC, especially its molecular subtype, and the need to calculate the personalized risk of development of metachronous tumors of the reproductive system in patients with the BC.

Zare S, Lin L, Alghamdi AG, et al.
Comparative Pathologic Analysis of Breast Cancers Classified as HER2/neu-Amplified by FISH Using a Standard HER2/CEP17 Dual Probe and an Alternative Chromosome 17 Control Probe.
Am J Surg Pathol. 2018; 42(9):1208-1215 [PubMed] Related Publications
At our institution, breast cancer cases that generate an equivocal HER2/neu (HER2) result by fluorescence in situ hybridization (FISH) using the dual HER2/chromosome enumeration probe (CEP17) are reflexed to an assay that utilizes an alternative control probe (lissencephaly gene1 [LIS1] [17p13.3]/retinoic acid receptor α [RARA] [17q21.2]). This study examines whether cancers that are classified as HER2-amplified with an alternate probe are clinicopathologically similar to those that are classified as such using the HER2/CEP17 probe. Reports for 1201 breast cancers were reviewed, and clinicopathologic findings were compared between HER2/CEP17-equivocal cases that became HER2-amplified using the alternate probe (group A: n=48), HER2-amplified cases using the HER2/CEP17 probe (group B: n=169), and HER2-nonamplified cases using the HER2/CEP17 probe (group C: n=910). Of 1201 cases tested using the HER2/CEP17 probe, 169 (14%) were HER2-amplified, 122 (10%) were equivocal, and 910 (76%) were nonamplified. Additional testing with the alternative probe on the 122 equivocal cases reclassified 48 (39%) of them to HER2-amplified, and such cases comprised 22% of all HER2-amplified tumors. A higher proportion of tumors with HER2 copy number between 5.0 and 5.9 became positive upon additional testing when compared with those with a priori HER2 copy numbers between 4.0 and 4.9 (P=0.0362). Group A cases, compared with group B cases, were more frequently positive for estrogen receptor (97.91% vs. 72.18%, P<0.0001) and progesterone receptor (85.41% vs. 59.17%, P=0.0009). Most group A cases (71%) were HER2 equivocal (score 2+) by immunohistochemistry, whereas most group B cases (60%) were positive (score 3+). Groups A and B showed no significant differences regarding patient age, lymph node status, tumor grade, histotype, and stage distribution. In summary, among our HER2-amplified cohort of breast cancers, alternative probe-detected cases were more frequently estrogen receptor and progesterone receptor positive than HER2/CEP17-detected cases, and were more frequently discordant with HER2 immunohistochemistry results. These findings raise the possibility of underlying biologic differences between these 2 groups, which warrants further study. However, the tumors were largely comparable regarding all other clinicopathologic variables. As it is unknown whether HER2-targeted therapy is truly beneficial in this subgroup of patients, future clinical trials should specifically evaluate this subset.

Wu L, Shi W, Long J, et al.
A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer.
Nat Genet. 2018; 50(7):968-978 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10

Morizane C, Ueno M, Ikeda M, et al.
New developments in systemic therapy for advanced biliary tract cancer.
Jpn J Clin Oncol. 2018; 48(8):703-711 [PubMed] Related Publications
Biliary tract cancer, carcinoma of the extrahepatic bile ducts, carcinoma of the gall bladder, ampullary carcinoma and intrahepatic cholangiocarcinoma are often identified at an advanced stage and have poor prognoses. Although effective chemotherapy regimens are needed, their development remains unsatisfactory. From the results of a phase III clinical trial (ABC-02 trial), gemcitabine plus cisplatin is the standard first-line chemotherapeutic regimen for advanced biliary tract cancer. A phase III trial of gemcitabine plus cisplatin vs. gemcitabine plus S-1 therapy (FUGA-BT) demonstrated the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin. A phase III trial of gemcitabine plus cisplatin vs. gemcitabine plus cisplatin plus S-1 (MITSUBA) was conducted, and the report on the results of the final analysis is being awaited. A standard second-line chemotherapeutic regimen has not yet been established. Fluoropyrimidines are frequently used in clinical practice. Despite many clinical trials being conducted with molecular targeted agents including erlotinib, cetuximab, panitumumab, bevacizumab, sorafenib, cediranib, trametinib and vandetanib, no agent has shown to be effective for advanced biliary tract cancer. Next-generation sequencing shows great promise by allowing rapid mutational analysis of multiple genes in human cancers, and attractive driver genetic alterations have been reported in biliary tract cancer. FGFR2 fusion gene, mutations of IDH1/2, BRAF, BRCA1/2, ATM, PIK3CA and overexpression of c-MET and HER2/neu are reported relatively frequently and are interesting targets. Therefore, future development in precision medicine utilizing next-generation sequencing is expected. Although the efficacy of immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1 and anti-CTLA4 antibodies, remains unknown at present, basic data and results of ongoing clinical trials are anticipated.

Good CR, Panjarian S, Kelly AD, et al.
TET1-Mediated Hypomethylation Activates Oncogenic Signaling in Triple-Negative Breast Cancer.
Cancer Res. 2018; 78(15):4126-4137 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Both gains and losses of DNA methylation are common in cancer, but the factors controlling this balance of methylation remain unclear. Triple-negative breast cancer (TNBC), a subtype that does not overexpress hormone receptors or HER2/NEU, is one of the most hypomethylated cancers observed. Here, we discovered that the TET1 DNA demethylase is specifically overexpressed in about 40% of patients with TNBC, where it is associated with hypomethylation of up to 10% of queried CpG sites and a worse overall survival. Through bioinformatic analyses in both breast and ovarian cancer cell line panels, we uncovered an intricate network connecting TET1 to hypomethylation and activation of cancer-specific oncogenic pathways, including PI3K, EGFR, and PDGF. TET1 expression correlated with sensitivity to drugs targeting the PI3K-mTOR pathway, and CRISPR-mediated deletion of TET1 in two independent TNBC cell lines resulted in reduced expression of PI3K pathway genes, upregulation of immune response genes, and substantially reduced cellular proliferation, suggesting dependence of oncogenic pathways on TET1 overexpression. Our work establishes TET1 as a potential oncogene that contributes to aberrant hypomethylation in cancer and suggests that TET1 could serve as a druggable target for therapeutic intervention.

Kjaergaard J, Hatfield S, Jones G, et al.
J Immunol. 2018; 201(2):782-791 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Tumor hypoxia-driven accumulation of extracellular adenosine was shown to facilitate tumor evasion by engaging the immunosuppressive, intracellular cAMP-elevating A

Swellam M, El Magdoub HM, Hassan NM, et al.
Potential diagnostic role of circulating MiRNAs in breast cancer: Implications on clinicopathological characters.
Clin Biochem. 2018; 56:47-54 [PubMed] Related Publications
BACKGROUND: Circulating miRNAs are stable in body fluids and resembles their levels in cancer tissue/cells. They have been expressed in many cancers among them is breast cancer. Authors aimed to investigate the expression levels of three circulating oncomiRNAs (miRNA-21, miRNA-222 and miRNA-373) in serum samples as a minimally non-invasive method for early detection of breast cancer, and study their relation with clinicopathological characters.
METHODS: MiRNAs expression levels were determined using quantitative real-time polymerase chain reaction (qPCR) in serum samples from three groups: primary breast cancer patients (n = 137), benign breast lesion patients (n = 60), and healthy individuals as control group (n = 38). Statistical analyses were carried out using SPSS.
RESULTS: Significant differences were observed between the expression levels of the studied miRNAs in the investigated groups, as their median levels were increased in breast cancer patients followed by benign group patients then the healthy individuals. MiRNA-373 reported the highest diagnostic efficacy as compared to miRNA-21 and miRNA-222 with high area under the curve (AUC equals 0.987). The relation between tested miRNAs and clinicopathological factors revealed significant difference with clinical stages and histological grades. Level of miRNA-21 and miRNA-373 were statistically significantly higher in invasive duct carcinoma (IDC) as compared to non-IDC. Similarly, their levels were increased in lymph node metastasis (P < 0.01). MiRNA-222 and miRNA-373 were significantly increased in positive PgR and positive Her-2/neu status, respectively.
CONCLUSION: Assessment of miRNAs in serum samples can be applied as minimally non-invasive markers for early detection of breast cancer, and as discriminator between different clinicopathological characters.

Park KU, Chen Y, Chitale D, et al.
Utilization of the 21-Gene Recurrence Score in a Diverse Breast Cancer Patient Population: Development of a Clinicopathologic Model to Predict High-Risk Scores and Response to Neoadjuvant Chemotherapy.
Ann Surg Oncol. 2018; 25(7):1921-1927 [PubMed] Related Publications
INTRODUCTION: The 21-gene expression profile [Oncotype DX Recurrence Score (RS)] stratifies benefit from adjuvant chemotherapy in hormone receptor (HR)-positive, HER2/neu-negative, node-negative breast cancer. It is not routinely applied to predict neoadjuvant chemotherapy (NACT) response; data in diverse patient populations also are limited. We developed a statistical model based on standard clinicopathologic features to identify high-risk cases (RS > 30) and then evaluated ability of predicted high RS to predict for NACT downstaging.
METHODS: Primary surgery patients with Oncotype DX RS testing 2012-2016 were identified from a prospectively-maintained database. A RS predictive model was created and applied to a dataset of comparable NACT patients. Response was defined as tumor size decrease ≥ 1 cm.
RESULTS: Of 394 primary surgery patients-60.4% white American; 31.0% African American-RS distribution was similar for both groups. No single feature reliably identified high RS patients; however, a model accounting for age, HR expression, proliferative index (MIB1/Ki67), histology, and tumor size was generated, with receiver operator area under the curve 0.909. Fifty-six NACT patients were identified (25 African American). Of 21 cases with all relevant clinicopathology, 14 responded to NACT and the model generated high-risk RS in 14 (100%); conversely, of 16 cases generating high-risk RS, only 2 did not respond.
CONCLUSIONS: Predictive modelling can identify high RS patients; this model also can identify patients likely to experience primary tumor downstaging with NACT. Until this model is validated in other datasets, we recommend that Oncotype-eligible patients undergo primary surgery with decisions regarding chemotherapy made in the adjuvant setting.

Castiello L, Sestili P, Schiavoni G, et al.
Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells.
Cancer Immunol Res. 2018; 6(6):658-670 [PubMed] Related Publications
Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu

Shi Y, Jia Y, Zhao W, et al.
Histone deacetylase inhibitors alter the expression of molecular markers in breast cancer cells via microRNAs.
Int J Mol Med. 2018; 42(1):435-442 [PubMed] Related Publications
Histone deacetylase inhibitors (HDACis) are able to suppress breast cancer cells in vitro and in vivo by altering the expression of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (Her2/neu). Since HDACis can alter the expression of various microRNAs (miRNAs/miRs), the present study aimed to examine the role of miRNAs in the effects of HDACis on breast cancer cells. We first examined the mRNA expression of ER, PR, and Her2/neu using RT-PCR and the protein levels of ER, PR, and Her2/neu using western blot analysis in MDA-MB-231 and BT474 cells, after trichostatin A (TSA) or vorinostat (SAHA) treatment. We then conducted miRNA expression profiling using microarrays after BT474 cells were treated with TSA or SAHA. Finally, we examined the effects of synthetic miR-762 and miR-642a-3p inhibitors on SAHA-induced downregulation of Her2/neu and SAHA-induced apoptosis and PARP cleavage in BT474 cells. The results indicated that TSA and SAHA dose‑dependently enhanced the mRNA and protein expression levels of ER and PR in MDA‑MB‑231 and BT474 cells. In addition, the mRNA expression levels of Her2/neu were reduced in MDA‑MB‑231 cells, and the mRNA and protein expression levels of Her2/neu were reduced in BT474 cells in response to SAHA and TSA. Furthermore, treatment with TSA (0.2 µM) or SAHA (5.0 µM) induced a marked alteration in the expression of various miRNAs in BT474 cells. Notably, when cells were cotransfected with miR‑762 and miR‑642a‑3p inhibitors, SAHA‑induced downregulation of Her2/neu was inhibited, and SAHA‑induced apoptosis and poly (ADP‑ribose) polymerase cleavage were significantly reduced in BT474 cells. These results indicated that numerous HDACi‑induced miRNAs are required to downregulate Her2/neu levels and promote apoptosis of Her2‑overexpressing breast cancer cells.

Oloomi M, Moazzezy N, Bouzari S
Modulation of Molecular Biomarker Expression in Response to Chemotherapy in Invasive Ductal Carcinoma.
Biomed Res Int. 2018; 2018:7154708 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Breast cancer (BC) has varied morphological and biological features and is classified based on molecular and morphological examinations. Molecular classification of BC is based on biological gene-expression profiling. In this study, biomarker modulation was assessed during BC treatment in 30 previously untreated patients. Heterogeneity among patients was pathologically diagnosed and classified into luminal and basal-like immunohistochemical profiles based on estrogen, progesterone, and human epidermal growth factor receptor (ER/PR/HER2) status. Marker heterogeneity was compared with mRNA biomarker expression in patients with BC before and after therapy. Reverse transcription-polymerase chain reaction was performed for molecular characterization. Expression and modulation of biological markers, CK19, hMAM, CEA, MUC, Myc, Ki-67, HER2/neu, ErbB2, and ER, were assessed after treatment, where the expression of the biomarkers CK19, Ki-67, Myc, and CEA was noted to be significantly decreased. Marker expression modulation was determined according to different stages and pathological characteristics of patients; coexpression of three markers (CK19, Ki-67, and Myc) was specifically modulated after therapy. In the histopathologically classified basal-like group, two markers (CK19 and Ki-67) were downregulated and could be considered as diagnostic biomarkers. In conclusion, pathological characteristics and marker variation levels can be evaluated to decide a personalized treatment for patients.

Mir R, Javid J, Al Balawi IA, et al.
A Germline Mutation in the BRCA1 3’UTR Variant Predicts Susceptibility to Breast Cancer in a Saudi Arabian Population
Asian Pac J Cancer Prev. 2018; 19(3):859-866 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Purpose: The impact of the BRCA1-3’UTR-variant on BRCA1 gene expression and altered responses to external stimuli was previously tested in vitro using a luciferase reporter assay. Its ability to predict breast cancer risk in women was also assessed but the conclusions were inconsistent. The present study concerns the relationship between the BRCA1-3’UTR germline variant rs8176318G>T and susceptibility to Breast cancer in an ethnic population of Saudi Arabia. Methodology: The study included 100 breast cancer patients and 100 sex matched healthy controls from the northwestern region (Tabuk) and Dammam of Saudi Arabia were investigated for the BRCA1-3’UTR germline variant rs8176318G>T using an allele specific PCR technique. Genotype distributions were then compared. Results: The frequencies of the three genotypes GG, TT and GT in our Saudi Arabian patients were 26%, 8% and 66% and in healthy controls were 45%, 5% and 50%, respectively (p=0.03). Risk of developing breast cancer was found to be significantly associated with the GT variant (OR 2.28, 1.24-4.191; RR 1.47, 1.11-1.93; P=0.007), GT+TT (OR, 2.32, 1.28-4.22; RR 1.48, 1.13-1.94; P=0.005) and the T allele (OR 1.62 , 1.072- 2.45; RR 1.28, 1.02-1.60: P=0.020). There were 2.76 and 2.28 fold increase risks of developing breast cancer associated with the TT and GT genotypes in our cases. A significant correlation was also found between the BRCA1 3’UTR variants with the stage of the disease and distant metastasis but not with age, grade, and ER, PR and her2/neu status. Conclusion : The rs8176318G/T in the 3’untranslated region (UTR) of the BRCA1 gene was found to be associatedwith increased susceptibility to breast cancer in our study population, increased risk being noted with the GT and TT genotypes. Further association studies are needed to confirm this finding in other regions of Saudi Arabia.

Wojciech S, Ahmad R, Belaid-Choucair Z, et al.
The orphan GPR50 receptor promotes constitutive TGFβ receptor signaling and protects against cancer development.
Nat Commun. 2018; 9(1):1216 [PubMed] Article available free on PMC after 01/04/2020 Related Publications
Transforming growth factor-β (TGFβ) signaling is initiated by the type I, II TGFβ receptor (TβRI/TβRII) complex. Here we report the formation of an alternative complex between TβRI and the orphan GPR50, belonging to the G protein-coupled receptor super-family. The interaction of GPR50 with TβRI induces spontaneous TβRI-dependent Smad and non-Smad signaling by stabilizing the active TβRI conformation and competing for the binding of the negative regulator FKBP12 to TβRI. GPR50 overexpression in MDA-MB-231 cells mimics the anti-proliferative effect of TβRI and decreases tumor growth in a xenograft mouse model. Inversely, targeted deletion of GPR50 in the MMTV/Neu spontaneous mammary cancer model shows decreased survival after tumor onset and increased tumor growth. Low GPR50 expression is associated with poor survival prognosis in human breast cancer irrespective of the breast cancer subtype. This describes a previously unappreciated spontaneous TGFβ-independent activation mode of TβRI and identifies GPR50 as a TβRI co-receptor with potential impact on cancer development.

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