scholarly journals Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand

2018 ◽  
Author(s):  
Remah Ali ◽  
Wells Brown ◽  
Stephen Conner Purdy ◽  
V. Jo Davisson ◽  
Michael K. Wendt
Keyword(s):  
Kinase Inhibitors ◽  
Mammary Epithelial Cells ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Egfr Signaling ◽  
Critical Pathway ◽  
Primary Tumors ◽  
Downstream Signaling ◽  
Induced Apoptosis

AbstractInhibition of EGFR signaling by small molecule kinase inhibitors and monocloncal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to EGF in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1 dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.

scholarly journals Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Gabriel L. Fiszman ◽  
María A. Jasnis
Keyword(s):  
Breast Cancer ◽  
Signaling Pathways ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Trastuzumab Resistance ◽  
Alternative Pathways ◽  
Downstream Signaling ◽  
Therapeutic Modalities

The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities.

scholarly journals HUNK phosphorylates EGFR to regulate breast cancer metastasis

Oncogene ◽  
2019 ◽  
Vol 39 (5) ◽  
pp. 1112-1124 ◽  
Author(s):  
Carly B. Williams ◽  
Kendall Phelps-Polirer ◽  
Ivan P. Dingle ◽  
Christina J. Williams ◽  
Matthew J. Rhett ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Metastasis ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Breast Cancers ◽  
Kinase Substrate ◽  
Downstream Signaling

Abstract Epidermal growth factor receptor (EGFR) is commonly over-expressed in metastatic breast cancer yet metastatic breast cancer is generally resistant to anti-EGFR therapies, and the mechanism for resistance to EGFR inhibitors in this setting is not fully understood. Hormonally up-regulated neu-associated kinase (HUNK) kinase is up-regulated in aggressive breast cancers and is thought to play a role in breast cancer metastasis. However, no studies have been conducted to examine a relationship between EGFR and HUNK in breast cancer metastasis. We performed a kinase substrate screen and identified that EGFR is phosphorylated by HUNK. Our studies show that HUNK phosphorylates EGFR at T654, enhancing receptor stability and downstream signaling. We found that increased phosphorylation of T654 EGFR correlates with increased epithelial to mesenchymal, migration and invasion, and metastasis. In addition, we found that HUNK expression correlates with overall survival and distant metastasis free survival. This study shows that HUNK directly phosphorylates EGFR at T654 to promote metastasis and is the first study to show that the phosphorylation of this site in EGFR regulates metastasis.

scholarly journals Prospective Study Evaluating the Impact of Tissue Confirmation of Metastatic Disease in Patients With Breast Cancer

2012 ◽  
Vol 30 (6) ◽  
pp. 587-592 ◽  
Author(s):  
Eitan Amir ◽  
Naomi Miller ◽  
William Geddie ◽  
Orit Freedman ◽  
Farrah Kassam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prospective Study ◽  
Treatment Plan ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Primary Tumors ◽  
Receptor Status ◽  
Metastatic Recurrence ◽  
The Impact

Purpose Decisions about treatment for women with metastatic breast cancer are usually based on the estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary tumor. Retrospective data suggest that discordance between primary and metastatic lesions leads to detrimental outcome. This prospective study investigated receptor status of primary tumors and metastases in the same patient and assessed the impact of discordance on patient management and survival. Patients and Methods Biopsies of suspected metastases were analyzed for ER, PgR, and HER2. Primary tumors and metastases were analyzed using similar methodology. The treating oncologist indicated a treatment plan before and after biopsy to determine whether the result influenced management. Patients were followed up for progression or death. Results Of 121 women undergoing biopsy, 80% could be analyzed for receptor status. Discordance in ER, PgR, and HER2 between the primary and the metastasis was 16%, 40%, and 10%, respectively. Biopsy led to a reported change of management in 14% of women (95% CI, 8.4% to 21.5%). Fine-needle aspiration and biopsy of bone led to reduced ability to analyze receptors. After a median follow-up of 12 months, there were no trends for an association between receptor discordance and either time to treatment failure or overall survival. Conclusion Biopsy of metastases is technically feasible. Clinicians alter immediate management in one of seven patients on the basis of results of the biopsy, and discordance is not then associated with detrimental effects on outcome. Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

scholarly journals DVL3 is over-expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
The United States ◽  
Breast Cancer Patients ◽  
Gene Encoding ◽  
Significant Differential Expression ◽  
Primary Tumors ◽  
Unbiased Manner

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published and public microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified significant differential expression of the gene encoding the Wnt pathway molecule dishevelled-3, DVL3 (5-7), in the primary tumors of breast cancer patients treated with trastuzumab. DVL3 expression in primary tumors of the breast in patients treated with trastuzumab was significantly higher than in patients not treated with trastuzumab.

scholarly journals DCC is differentially expressed in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Messenger Rna ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
The United States ◽  
Differentially Expressed ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Deleted In Colorectal Cancer

Trastuzumab (Herceptin) is a monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) (1) utilized for the treatment of adjuvant and metastatic breast cancer (2) in the United States and worldwide. We mined published microarray and gene expression data (3, 4) to discover in an unbiased manner the most striking transcriptional features of trastuzumab treatment. We identified the deleted in colorectal cancer locus DCC (5, 6) as among the genes most differentially expressed in the primary tumors of patients with breast cancer treated with trastuzumab. The primary tumors of breast cancer patients treated with trastuzumab expressed higher levels of DCC messenger RNA than did patients not treated with trastuzumab, and a single administration of trastuzumab was sufficient to result in differential expression of DCC in primary tumors of the breast, demonstrating that a gene encoding for a netrin receptor, cellular machinery utilized for axon guidance in the central nervous system (5-9), is transcriptionally induced in primary tumors of the breast following treatment with trastuzumab.

Detection of estrogen receptor in bone marrow from patients with metastatic breast cancer.

1987 ◽  
Vol 5 (11) ◽  
pp. 1779-1782 ◽  
Author(s):  
U Berger ◽  
J L Mansi ◽  
P Wilson ◽  
R C Coombes
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Endocrine Therapy ◽  
Tumor Cells ◽  
Epithelial Membrane Antigen ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Double Staining ◽  
Primary Tumors ◽  
Er Positive

We devised a method of detecting estrogen receptors (ER) in bone marrow metastases from patients with breast cancer. The method involves a sequential double-staining immunocytochemical technique, with a monoclonal antibody to ER and a polyclonal antibody recognizing epithelial membrane antigen to confirm the epithelial nature of suspected tumor cells. Twenty-seven patients were assessed: ten were found to have ER-positive tumor cells in the bone marrow; ten had ER-negative cells; and the remaining seven patients had no tumor cells in the bone marrow smears. Of the ten patients with ER-positive cells, eight (80%) either had a response to endocrine therapy, implying that they possess ER-positive breast cancers, or had ER-positive primary tumors as determined by the dextran-coated charcoal biochemical assay (DCC). Of the ten patients with ER-negative cells in the bone marrow, eight failed to respond to endocrine therapy. This technique therefore provides a means of predicting which patients will respond to endocrine therapy, and is particularly important in those patients whose ER status is unknown.

Effects of EGF-R on Transcription Factor Activation in Hematopoietic Cells: EGF-R Activates Multiple Transcription Factors Which Induce Proliferation in the Absence of Autocrine Cytokines.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4185-4185
Author(s):  
John G. Shelton ◽  
Linda S. Steelman ◽  
Martin McMahon ◽  
James A. McCubrey
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Kinase Inhibitors ◽  
Hematopoietic Cells ◽  
Growth Factor Receptor ◽  
Biological Properties ◽  
Small Molecular Weight ◽  
Erythroid Progenitor ◽  
Jnk Inhibitors ◽  
Induced Apoptosis

Abstract v-ErbB is an oncogene related to the Epidermal Growth Factor Receptor (EGF-R) that was initially discovered in the genome of avian erythoblastosis virus. v-ErbB will abrogate the requirement of erythroid progenitor cells for erythropoietin and stem cell factor and block terminal differentiation. EGF-R overexpression has been observed in many pathological situations and the EGF-R gene is amplified in certain tumors. Moreover, there is a truncated form of EGF-R referred to as EGFvIII which resembles v-ErbB in biological properties. One problem frequently encountered in studying the effects of EGF-R overexpression in many tumors is that EGF-R expression is often constitutive and in the presence of increased expression of other oncogenes or in the absence of certain tumor suppressor genes. To circumvent these problems, we subcloned v-ErbB into a vector which contained the estrogen receptor hormone binding domain which renders the v-ErbB protein dependent upon the addition of beta-estradiol or 4 OH tamoxifen for activity. The v-ErbB:ER oncogene will conditionally abrogate the cytokine dependence of human (TF-1) and murine (FL5.12 and FDC-P1) hematopoietic cells efficiently. This construct has allowed us to examine the transcription factors pathways activated by v-ErbB:ER in hematopoietic cells which are required for proliferation in the absence of previously required cytokines. By determining which signal transduction pathways were activated in response to either v-ErbB:ER activation or IL-3 addition in the presence and absence of specific small molecular weight membrane permeable kinase inhibitors, we could ascertain that v-ErbB:ER expression activated the STAT5, Elk, CREB, Jun, and Forkhead (Foxo) family of transcription factors in FL/v-ErbB:ER cells. The activation of these transcription factors was blocked by the respective kinase inhibitors. Thus v-ErbB:ER activated a broad spectrum of transcription factors. Treatment of v-ErbB:ER cells with the EGF-R inhibitor AG1478 very efficiently induced apoptosis in these cells at 100 to 1000 fold lower concentrations than MEK, PI3K or JNK inhibitors and activation of all these transcription factor inhibitors was inhibited. In contrast, when the cells were treated with MEK, PI3K or JNK inhibitors, only the transcription factors specific for the individual pathways were inhibited. FL5.12 cells conditionally transformed to grow in response to activated Raf and Akt, (FL/Akt:ER+Raf-1:AR) were also isolated. Activation of STAT5 by either Raf or Akt did not occur in FL/Akt:ER+Raf-1:AR cells, but did occur when the cells were treated with IL-3. Furthermore, Elk activation occurred in response to Raf activation but not IL-3 stimulation in the FL/Akt:ER+Raf-1:AR cells which grew in response to Raf and Akt. Thus oncogenes such as v-ErbB:ER, which are more effective in their ability to transform hematopoietic cells than oncogenes such as Raf and Akt, can induce multiple transcription factors, only some of which are required for growth in tissue culture systems.

The ERB family receptor dimerization in glioblastoma—An eTag assay analysis of 23 cases

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1582-1582
Author(s):  
M. R. Hameed ◽  
L. Sharer ◽  
E. Cho ◽  
S. Aisner ◽  
L. Cao ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Driving Forces ◽  
Growth Factor Receptor ◽  
Signaling Molecules ◽  
Egfr Signaling ◽  
Fluorescent Reporter ◽  
Downstream Signaling ◽  
Egfr Signaling Pathway ◽  
Ffpe Tumor ◽  
Her 2

1582 Background: Glioblastoma is the most malignant astrocytic tumor and accounts for about 50–60% of all astrocytic neoplasms. Despite intensive radiation and chemotherapy, less than 2% of patients survive more than 3 years. The Erb family of signaling molecules are transmembrane receptors with intrinsic kinase activity (except ErbB3) capable of modifying tyrosine residues on the receptor itself as well as on downstream signaling molecules. Under physiological conditions a variety of ligands interact and act as driving forces in the formation of homo and heterodimeric complexes between the four receptors leading to signal amplification and downstream activities. More than one third of glioblastoma cases show gene amplification of epidermal growth factor receptor (EGFR) which can be in truncated or rearranged form. The eTag assay system (Monogram) is an antibody based fluorescent assay that has the potential to assess the activation state of the EGFR signaling pathway. Methods: Twenty three cases of glioblastoma were selected for eTag analysis. There were twelve males and eleven females with ages ranging from 20–84 years. After reviewing the histology, 10 micron sections were cut from formalin fixed paraffin embedded (FFPE) tumor tissue blocks. Specific monoclonal antibodies of the Erb family bound to a fluorescent reporter (eTag) were applied to tissue sections. After binding of specific analyte, a second monoclonal antibody is added which acts as molecular scissors resulting in cleavage of “eTags”. The released eTag molecules are separated by capillary electrophoresis and measured as relative fluorescent units. Various FFPE tumor cell lines were used as controls. Results: Nineteen out of twenty three tumors (82%) showed the presence of dimers of the Erb family signaling pathway. High levels of intra and /or extracellular EGFR homodimers (HER-1-HER-1) were detected in eight samples (35%). EGFR-HER-3 dimers and EGFR-HER-2 dimers were seen at high levels in four and six samples (17% and 26% respectively). High levels of HER-2-HER3 dimers were detected in six samples (26%). Conclusion: The EGFR signaling pathway plays a substantial role in tumorigenesis of glioblastoma. Identification of receptor homo and heterodimers may be of value during treatment planning of individual patients. No significant financial relationships to disclose.

Sign in / Sign up

Export Citation Format

Share Document