The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Hsu, Jennifer L.; Hung, Mien‐Chie

doi:10.1007/s10555-016-9649-6

Cited by 311 publications

(216 citation statements)

References 202 publications

(195 reference statements)

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“…Epidermal Growth Factor Receptor (EGFR) is frequently overexpressed in triple negative breast cancers (TNBCs, negative for expression of estrogen receptor (ER) and progesterone receptor (PR), and lacking amplification of the human epidermal growth factor receptor-2 ( HER2 ) gene), and its overexpression is associated with poor clinical outcomes [1–3]. EGFR and its downstream signaling pathways regulate many aspects of cell behavior associated with tumor growth and progression, including cell proliferation, survival, epithelial-to-mesenchymal transition (EMT), migration, invasion, and drug resistance [4–13].…”

Section: Introductionmentioning

confidence: 99%

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Wise

Żółkiewska

2017

Breast Cancer Res Treat

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Purpose The CD44+/CD24− cell phenotype is enriched in triple negative breast cancers (TNBCs), is associated with tumor invasive properties, and serves as a cell surface marker profile of breast cancer stem-like cells. Activation of Epidermal Growth Factor Receptor (EGFR) promotes the CD44+/CD24− phenotype, but the specific signaling pathway downstream of EGFR responsible for this effect is not clear. The purpose of this study was to determine the role of the MEK/ERK pathway in the expansion of CD44+/CD24− populations in TNBC cells in response to EGFR activation. Methods Representative TNBC cell lines SUM159PT (claudin-low) and SUM149PT (basal) were used to evaluate cell surface expression of CD44 and CD24 by flow cytometry in response to EGFR and MEK inhibition or activation. EGFR and ERK phosphorylation levels were analyzed by Western blotting. The relationship between EGFR phosphorylation and MEK activation score in basal and claudin-low tumors from the TCGA database was examined. Results Inhibition of ERK activation with selumetinib, a MEK1/2 inhibitor, blocked EGF-induced expansion of CD44+/CD24− populations. Sustained activation of ERK by overexpression of constitutively active MEK1 was sufficient to expand CD44+/CD24− populations in cells in which EGFR activity was blocked by either erlotinib, an EGFR kinase inhibitor, or BB-94, a metalloprotease inhibitor that prevents generation of soluble EGFR ligands. In basal and claudin-low tumors from the TCGA database, there was a positive correlation between EGFR_pY1068 and MEK activation score in tumors without genomic loss of DUSP4, a negative regulator of ERK, but not in tumors harboring DUSP4 deletion. Conclusion Our results demonstrate that ERK activation is a key event in EGFR-dependent regulation of CD44+/CD24− populations. Furthermore, our findings highlight the role of ligand-mediated EGFR signaling in the control of MEK/ERK pathway output in TNBC tumors without DUSP4 loss.

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Section: Introductionmentioning

confidence: 99%

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Wise

Żółkiewska

2017

Breast Cancer Res Treat

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“…Protein levels of ERBB2 dimerization partners ERBB3 and ERBB4, as well as phospho-ERBB3, were also significant under-expressed in all three proposed false positive-samples when compared to the pCR cases (ERBB3 protein: p=0.0097, ERBB3 phosphoprotein: p=0.0318, ERBB4 protein: p=0.0131) ( Figure 3E). In contrast, protein and phosphoprotein levels of EGFR, the remaining dimerization partner of ERBB2, does not appear to be correlated with ERBB2 levels and was high in the non-pCR samples, suggesting that EGFR homodimers may play a driver role in signaling when ERBB2 is low 22,23 .…”

Section: Proteogenomic Analysis Of the Erbb2 Locus Suggests False Posmentioning

confidence: 83%

Microscaled Proteogenomic Methods for Precision Oncology

Satpathy

Jaehnig

Krug

et al. 2019

Preprint

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and MJE: Matthew.Ellis@bcm.edu Running title: Microscaled Proteogenomic Methods for Precision Oncology Satpathy et al., Microscaled Proteogenomic Methods for Precision Oncology 2 AbstractCancer proteogenomics integrates genomics, transcriptomics and mass spectrometry (MS)-based proteomics to gain insights into cancer biology and treatment efficacy. A proteogenomics approach was therefore developed for frozen core biopsies using tissue-sparing specimen processing with a "microscaled" proteomics workflow. For technical proof-of-principle, biopsies from ERBB2 positive breast cancers before and 48-72 hours after the first dose of neoadjuvant trastuzumabbased chemotherapy were analyzed. ERBB2 protein and phosphosite levels, as well as mTOR target phosphosites, were significantly more suppressed upon treatment in cases associated with pathological complete response, suggesting MS-based pharmacodynamics is achievable. Furthermore, integrated analyses indicated potential causes of treatment resistance including the absence of ERBB2 amplification (false-ERBB2 positive) and insufficient ERBB2 activity for therapeutic sensitivity despite ERBB2 amplification (pseudo-ERBB2 positive). Candidate resistance features in true-ERBB2+ cases, including androgen receptor signaling, mucin expression and an inactive immune microenvironment were observed. Thus, proteogenomic analysis of needle core biopsies is feasible and clinical utility should be investigated. enriched PDX (WHIM) models with ERBB2 protein expression. B. MUC1 immunohistochemistry (IHC) of WHIM8, WHIM35 and BCN1369.

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“…The EGFR is a receptor tyrosine kinase, it not only regulates cell proliferation and survival, but also promotes the invasion and migration of tumor cells (Hsu and Hung, 2016;Sigismund et al, 2018). EGFR usually performs its biological functions via activation of PLC-γ1-PKC, MAPK-MEK-ERK, and PI3K-Akt-mTOR signaling pathways (Lee et al, 2010;Huang et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

Niu

Wang

Liang

et al. 2019

Cell Biology International

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Phosphoinositide 3‐kinase (PI3K) signaling is frequently deregulated in breast cancer and plays a critical role in tumor progression. However, resistance to PI3K inhibitors in breast cancer has emerged, which is due to the enhanced β‐catenin nuclear accumulation. Until now, the mechanisms underlying PI3K inhibition‐induced β‐catenin nuclear accumulation remains largely unknown. In the present study, we found inhibition of PI3K with LY294002 promoted β‐catenin nuclear accumulation in MCF‐7 and MDA‐MB‐231 breast cancer cells. Combining PI3K inhibitor LY294002 with XAV‐939, an inhibitor against β‐catenin nuclear accumulation, produced an additive anti‐proliferation effect against breast cancer cells. Subsequent experiments suggested β‐catenin nuclear accumulation induced by PI3K inhibition depended on the feedback activation of epidermal growth factor receptor (EGFR) signaling pathway in breast cancer cells. Inhibition of EGFR phosphorylation with Gefitinib enhanced anti‐proliferation effect of PI3K inhibitor LY294002 in MCF‐7 and MDA‐MB‐231 cells. Taken together, our findings may elucidate a possible mechanism explaining the poor outcome of PI3K inhibitors in breast cancer treatment.

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The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Cited by 311 publications

References 202 publications

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Metalloprotease-dependent activation of EGFR modulates CD44+/CD24− populations in triple negative breast cancer cells through the MEK/ERK pathway

Microscaled Proteogenomic Methods for Precision Oncology

Suppression of epidermal growth factor receptor‐mediated β‐catenin nuclear accumulation enhances the anti‐tumor activity of phosphoinositide 3‐kinase inhibitor in breast cancer

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