EGFR isoforms and gene regulation in human endometrial cancer cells

Lina Albitar; Gavin Pickett; Marilee Morgan; Jason A. Wilken; Nita J. Maihle; Kimberly K. Leslie

doi:10.1186/1476-4598-9-166

EGFR isoforms and gene regulation in human endometrial cancer cells

Lina Albitar, Gavin Pickett, Marilee Morgan, Jason A. Wilken, Nita J. Maihle, Kimberly K. Leslie

Research output: Contribution to journal › Article › peer-review

46 Scopus citations

Abstract

Background: Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation.Results: We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells.Conclusions: Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.

Original language	English (US)
Article number	166
Journal	Molecular cancer
Volume	9
DOIs	https://doi.org/10.1186/1476-4598-9-166
State	Published - Jun 25 2010
Externally published	Yes

ASJC Scopus subject areas

Molecular Medicine
Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1186/1476-4598-9-166

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title = "EGFR isoforms and gene regulation in human endometrial cancer cells",

abstract = "Background: Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation.Results: We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells.Conclusions: Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.",

author = "Lina Albitar and Gavin Pickett and Marilee Morgan and Wilken, {Jason A.} and Maihle, {Nita J.} and Leslie, {Kimberly K.}",

note = "Funding Information: We thank AstraZeneca for providing gefitinib. Support also was provided by the Keck-UNM Genomics Resource (KUGR), Facility of the UNM Cancer Research and Treatment Center, the WM Keck Foundation, and the State of New Mexico. The authors would like to thank Dr. Jill Reiter (Yale University) for technical comments/discussions related to this manuscript and Dr. Suzy Davies for assisting with the review of the manuscript. This work was supported by NIH grant R01CA99908 to K.K.L. and N.J.M., NIH CA27469, Gynecologic Oncology Group Core Laboratory for Receptors to K.K.L., NIH CA79808 to N.J.M., a Cancer Research Postdoctoral Fellowship from the Ladies Auxiliary to the Veterans of Foreign Wars to J.A.W., a grant from the Elsa U. Pardee Foundation to J.A.W., the Cory Beach Foundation, and donations from Mrs. Shirley Leslie and Dean and Alice Irvin to K.K.L.",

year = "2010",

month = jun,

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doi = "10.1186/1476-4598-9-166",

language = "English (US)",

volume = "9",

journal = "Molecular cancer",

issn = "1476-4598",

publisher = "BioMed Central",

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TY - JOUR

T1 - EGFR isoforms and gene regulation in human endometrial cancer cells

AU - Albitar, Lina

AU - Pickett, Gavin

AU - Morgan, Marilee

AU - Wilken, Jason A.

AU - Maihle, Nita J.

AU - Leslie, Kimberly K.

N1 - Funding Information: We thank AstraZeneca for providing gefitinib. Support also was provided by the Keck-UNM Genomics Resource (KUGR), Facility of the UNM Cancer Research and Treatment Center, the WM Keck Foundation, and the State of New Mexico. The authors would like to thank Dr. Jill Reiter (Yale University) for technical comments/discussions related to this manuscript and Dr. Suzy Davies for assisting with the review of the manuscript. This work was supported by NIH grant R01CA99908 to K.K.L. and N.J.M., NIH CA27469, Gynecologic Oncology Group Core Laboratory for Receptors to K.K.L., NIH CA79808 to N.J.M., a Cancer Research Postdoctoral Fellowship from the Ladies Auxiliary to the Veterans of Foreign Wars to J.A.W., a grant from the Elsa U. Pardee Foundation to J.A.W., the Cory Beach Foundation, and donations from Mrs. Shirley Leslie and Dean and Alice Irvin to K.K.L.

PY - 2010/6/25

Y1 - 2010/6/25

N2 - Background: Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation.Results: We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells.Conclusions: Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.

AB - Background: Epidermal growth factor (EGF) and its receptor (EGFR) constitute a principal growth-promoting pathway in endometrial cancer cells. Pre-clinical studies were undertaken to compare the expression of EGFR isoforms and the downstream effects of activating or blocking EGFR function in Ishikawa H cells, derived from a moderately differentiated type I endometrioid adenocarcinoma, or in Hec50co cells, derived from a poorly differentiated type II adenocarcinoma with papillary serous sub-differentiation.Results: We investigated whether EGFR mutations are present in the tyrosine kinase domain (exons 18-22) of EGFR and also whether EGFR isoforms are expressed in the Ishikawa H or Hec50co cell lines. Sequence of the EGFR tyrosine kinase domain proved to be wild type in both cell lines. While both cell lines expressed full-length EGFR (isoform A), EGFR and sEGFR (isoform D) were expressed at significantly lower levels in Hec50co cells compared to Ishikawa H cells. Analysis of gene expression following EGF vs. gefitinib treatment (a small molecule EGFR tyrosine kinase inhibitor) was performed. Early growth response 1, sphingosine kinase 2, dual specificity phosphatase 6, and glucocorticoid receptor DNA binding factor 1 are members of a cluster of genes downstream of EGFR that are differentially regulated by treatment with EGF compared to gefitinib in Ishikawa H cells, but not in Hec50co cells.Conclusions: Type I Ishikawa H and type II Hec50co endometrial carcinoma cells both express EGFR and sEGFR, but differ markedly in their responsiveness to the EGFR inhibitor gefitinib. This difference is paralleled by differences in the expression of sEGFR and EGFR, as well as in their transcriptional response following treatment with either EGF or gefitinib. The small cluster of differently regulated genes reported here in these type I vs. type II endometrial cancer-derived cell lines may identify candidate biomarkers useful for predicting sensitivity to EGFR blockade.

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EGFR isoforms and gene regulation in human endometrial cancer cells

Abstract

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UN SDGs

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