ErbB receptors: from oncogenes to targeted cancer therapies

Zhang, Hongtao; Berezov, Alan; Wang, Qiang; Zhang, Geng; Drebin, Jeffrey A.; Murali, Ramachandran; Greene, Mark I.

doi:10.1172/jci32278

Cited by 492 publications

(379 citation statements)

References 109 publications

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“…The concept of EGFR dimerization is based on the stabilization of asymmetric dimers between the kinases. The C-terminus from one kinase and the N-terminus from the other kinase are responsible for the formation of an asymmetric dimer (67)(68)(69). Using this EGFR mutant (1706Q, V948R) with labeled EGFR revealed a decrease in normalized dimer amount to 28%, which is significantly lower than the 57% dimer fraction in control experiments.…”

Section: Discussionmentioning

confidence: 88%

The Epidermal Growth Factor Receptor Forms Location-Dependent Complexes in Resting Cells

Yavas

Macháň

Wohland

2016

Biophysical Journal

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The epidermal growth factor receptor (EGFR) is a prototypical receptor tyrosine kinase involved in cell growth and proliferation and associated with various cancers. It is commonly assumed that after activation by binding of epidermal growth factor to the extracellular domain it dimerizes, followed by autophosphorylation of tyrosine residues at the intracellular domain. However, its oligomerization state before activation is controversial. In the absence of ligands, EGFR has been found in various, inconsistent amounts of monomeric, inactive dimeric, and oligomeric forms. In addition, evidence suggests that the active conformation is not a simple dimer but contains higher oligomers. As experiments in the past have been conducted at different conditions, we investigate here the influence of cell lines (HEK293, COS-7, and CHO-K1), temperature (room temperature and 37 C), and membrane localization on the quantitation of preformed dimers using SW-FCCS, DC-FCCS, quasi PIE-FCCS, and imaging FCCS. While measurement modality, temperature, and localization on upper or lower membranes have only a limited influence on the dimerization amount observed, the cell line and location to periphery versus center of the cell can change dimerization results significantly. The observed dimerization amount is strongly dependent on the expression level of endogenous EGFR in a cell line and shows a strong cell-to-cell variability even within the same cell line. In addition, using imaging FCCS, we find that dimers have a tendency to be found at the periphery of cells compared to central positions.

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Section: Discussionmentioning

confidence: 88%

The Epidermal Growth Factor Receptor Forms Location-Dependent Complexes in Resting Cells

Yavas

Macháň

Wohland

2016

Biophysical Journal

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“…It has been shown to have an important function in the growth and survival of tumor cells, including processes such as cellular growth, apoptosis, metastasis, and angiogenesis (Zhang et al, 2007;Capdevila et al, 2009). We have found that PA-MSHA preferentially inhibited the proliferation of breast cancer cell lines, which are all EGFR-positive.…”

Section: Introductionmentioning

confidence: 75%

Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner

Liu

Hou

Zhu³

et al. 2010

Oncogene

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To identify more therapeutic targets and clarify the detailed mechanisms of Pseudomonas aeruginosa-mannosesensitive hemagglutinin (PA-MSHA) on breast cancer cells both in vitro and in vivo. PA-MSHA was administered to epidermal growth factor receptor (EGFR)-positive human breast cancer cell lines MDA-MB-231HM and MDA-MB-468 in vitro and to mice bearing tumor xenografts. The mannose cocultured test was used to detect the effect of mannose on PA-MSHA-induced cell proliferation, cell cycle arrest, apoptosis, and EGFR pathway signaling. We found that cells stimulated with PA-MSHA exhibited a downregulation of EGFR signaling. The addition of mannose partially inhibited the PA-MSHA-stimulated cell anti-proliferative effect, cell apoptosis, cell cycle arrest, activation of apoptosis-associated caspases, and even downregulation of the EGFR signaling pathway. In vivo, PA-MSHA treatment significantly suppressed mammary tumorigenesis in xenografts in mice and decreased lung metastasis in MDA-MB-231HM celltransplanted mice. Tumor sample analyses confirmed inhibition of the EGFR pathway in the PA-MSHAtreated mice. In conclusion, this study showed that the involvement of the mannose-mediated EGFR pathway has a critical function in the preclinical rationale for the development of PA-MSHA for the treatment of human breast cancer. It also suggests the potentially beneficial use of PA-MSHA in adjuvant therapy for breast tumors with EGFR overexpression.

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“…We and others (Guy et al, 1992;Tan et al, 1997Tan et al, , 2005Tan et al, , 2006aTan et al, , 2006b) have previously shown that the overexpression of ErbB2 increases the transformation and/ or metastatic potentials of breast cancer cells. In addition, ErbB2 has been shown to activate signaling molecules that regulate bioenergetic metabolism, such as Ras, PI3K/Akt, mTOR and Src (Yarden and Sliwkowski, 2001;Zhou et al, 2004;Tan et al, 2005Tan et al, , 2006bZhang et al, 2007). A recent study investigated the role of lactate dehydrogenase A (LDH-A), a critical enzyme in the glycolysis pathway, in the tumor maintenance of neu-transformed mouse mammary epithelial cells, showing that compared to normal cells, cancer cells have deregulated bioenergetic metabolism and increased glycolysis (Fantin et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

et al. 2009

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ErbB2 has been shown to activate signaling molecules that may regulate glucose metabolism. However, there is no evidence reported to directly link ErbB2 to glycolysis, and the mechanism underlying ErbB2-enhanced glycolysis is poorly understood. In this study, we investigated the role and mechanism of ErbB2 in regulating glycolysis. We found that ErbB2-overexpressing cells possessed a significantly higher level of glycolysis when compared to the ErbB2-low-expressing cells, and the downregulation of ErbB2 markedly decreased glycolysis. Overexpression of ErbB2 increased the expression of glycolysis-regulating molecules lactate dehydrogenase A (LDH-A) and heat shock factor 1 (HSF1). ErbB2 activated HSF1, indicated by the increased HSF1 trimer formation, and promoted HSF1 protein synthesis. HSF1 bound to LDH-A promoter and the downregulation of HSF1 reduced the expression of LDH-A and subsequently decreased cancer cell glycolysis and growth. Moreover, the glycolysis inhibitors, 2-deoxyglucose and oxamate, selectively inhibited the growth of ErbB2-overexpressing cells. Taken together, this study shows that in human breast cancer cells, ErbB2 promotes glycolysis at least partially through the HSF1-mediated upregulation of LDH-A. This pathway may have a major role in regulating glucose metabolism in breast cancer cells. These novel findings have important implications for the design of new approaches to target ErbB2-overexpressing breast cancers.

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ErbB receptors: from oncogenes to targeted cancer therapies

Cited by 492 publications

References 109 publications

The Epidermal Growth Factor Receptor Forms Location-Dependent Complexes in Resting Cells

The Epidermal Growth Factor Receptor Forms Location-Dependent Complexes in Resting Cells

Inhibition of EGFR pathway signaling and the metastatic potential of breast cancer cells by PA-MSHA mediated by type 1 fimbriae via a mannose-dependent manner

Upregulation of lactate dehydrogenase A by ErbB2 through heat shock factor 1 promotes breast cancer cell glycolysis and growth

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