The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer

McIntyre, Emmet; Blackburn, E. K.; Brown, Philip J.; Johnson, Colin G.; Gullick, William J.

doi:10.1007/s10549-009-0536-5

Cited by 46 publications

(36 citation statements)

References 14 publications

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“…The Lapatinib-TKI, however, has been developed rather to reversibly inhibit kinase activity of both the Her2 and the epidermal growth factor receptor (EGFR; 20,21). However, counter-productive stimulation of receptor activation and cell proliferation by native ErbB receptor-related growth factors, a phenomenon that is likely to play a significant role in vivo (22,23), has not yet been systematically investigated.…”

mentioning

confidence: 99%

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

et al. 2011

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Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor-and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRGcaused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. '

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confidence: 99%

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

et al. 2011

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“…Brand et al (2013) reported that HER3 is expressed in the nucleus of breast (SKBR-3, MCF-7, BT-474, HCC-1954 and BT-549), lung (H-226), head and neck (SCC-6 and CCS-1) and colon (LoVo and Caco-2) cell lines. The disruption of HER receptors occurs by a variety of mechanisms, especially receptor overexpression (Mendelsohn, Baselga, 2003;Herbst, Heymach, Lippman, 2008;Lee et al, 2014), overproduction of agonists, receptor overexpression associated with overproduction of ligands, which results in autocrine activation (Mcintyre et al, 2010), mutations that cause constitutive activation of the tyrosine kinase domain (Jaiswal et al, 2013) and endocytosis defects during receptor internalization (Abella, Park, 2009). …”

Section: Malignancy and Development Of Resistancementioning

confidence: 99%

“…In breast cancer, overexpression of HER2 correlates with poor prognosis, resistance to hormonal treatment and severity of malignancy, and shows correlations with mutations in p53 protein (Mendelsohn, Baselga, 2003;Lassus et al, 2006;Seoane et al, 2010). Many ligands, including NRG variants, are overexpressed, suggesting the possibility of autocrine signaling (Mcintyre et al, 2010). In diffuse types of gastric tumors, immunohistochemistry and fluorescence in situ hybridization (FISH) analysis demonstrated that 21-32% of European and Asian patients exhibited HER2 overexpression (Bang et al, 2010).…”

Section: Malignancy and Development Of Resistancementioning

confidence: 99%

“…Indeed, the search for alterations in breast cancers revealed that HER2 is up to 100-fold higher in 25-30% of invasive breast cancers, whereas 10-20% are triple-negative, negative for estrogen and progesterone receptors and without overexpression of HER2 (Lee et al, 2014). All HER members are overexpressed in a wide variety of breast cancers, basically, in the following order: HER2> HER1> HER3> HER4 (Mcintyre et al, 2010). Breast cancers can express from 25 to 50 copies of HER genes and up to 2 million receptors per cell.…”

Section: Treatment: From Surgery To the Re-ceptormentioning

confidence: 99%

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Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

Ferreira

Pessoa

2017

Braz. J. Pharm. Sci.

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“…Conceptually, the complex and interactive mechanisms of actions of the EGFR family, justifies investigation of all four receptors of the EGF family as an entity [18]- [20] as a supplement to the studies describing the receptors individually. Comparative studies exist on the HER2 expression in the primary tumors, lymph node metastases, and distant metastases [21]- [24].…”

Section: Introductionmentioning

confidence: 99%

Expression of the Epidermal Growth Factor Receptors and Ligands in Paired Samples of Normal Breast Tissue, Primary Breast Carcinomas and Lymph Node Metastases

Brügmann¹,

Jensen²,

Garne³

et al. 2014

ABCR

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Purpose: In breast cancer, the EGF receptors host an increasing number of therapeutic targets and the interactive mechanisms of actions of the receptors and their ligands justify investigation of the EGF family as an entity. Experimental design: Paired tissue samples of normal breast tissue and primary breast carcinomas were examined in a prospective study of 163 patients. A third sample was obtained from the paired ipsilateral metastatic lymph node from 58 of these patients. The mRNA expression of four EGF receptors (HER1 -HER4) and 11 activating ligands was quantified with real-time RT-PCR. Results: Expression of HER2, HER3, and HER4 mRNA was upregulated in primary carcinomas compared to normal breast tissue while HER1 was downregulated. The mRNA expression of HER3 and HER4 differed between primary breast carcinomas and lymph node metastases whereas there was no difference in the expression of HER1 and HER2. The combination of low HER3 and low HER4 expression in the primary carcinoma was significantly more frequent in lymph node-negative patients as compared to lymph node positive patients. Distinct correlation patterns of the receptors and their corresponding activating ligands appeared in both normal breast tissue and in carcinomas, notably for the HER3 and HER4 receptors and their 3 specific ligands: HB-EGF, NRG2, and NRG4. Conclusion: HER2, HER3, and HER4 showed increased mRNA expression in carcinomas and were positively correlated to each other and to specific activating ligands. Furthermore, low HER3 and HER4 expression in the carcinomas correlated to the absence of lymph node metastases.

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The complete family of epidermal growth factor receptors and their ligands are co-ordinately expressed in breast cancer

Cited by 46 publications

References 14 publications

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

Molecular biology of human epidermal receptors, signaling pathways and targeted therapy against cancers: new evidences and old challenges

Expression of the Epidermal Growth Factor Receptors and Ligands in Paired Samples of Normal Breast Tissue, Primary Breast Carcinomas and Lymph Node Metastases

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