ERE-independent ERα target genes differentially expressed in human breast tumors

Christine Glidewell-Kenney; Jeffrey Weiss; Eun Jig Lee; Suresh Pillai; Toshio Ishikawa; Eric A. Ariazi; J. Larry Jameson

doi:10.1016/j.mce.2005.10.003

ERE-independent ERα target genes differentially expressed in human breast tumors

Christine Glidewell-Kenney, Jeffrey Weiss, Eun Jig Lee, Suresh Pillai, Toshio Ishikawa, Eric A. Ariazi, J. Larry Jameson^*

^*Corresponding author for this work

Medicine, Endocrinology Division

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

28 Scopus citations

Abstract

The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERα can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-κB) at their cognate sites on DNA. We previously generated a mutant form of ERα (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERα into MDA-MB231 ERα-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17β-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERα pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERα responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERα pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERα target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.

Original language	English (US)
Pages (from-to)	53-59
Number of pages	7
Journal	Molecular and Cellular Endocrinology
Volume	245
Issue number	1-2
DOIs	https://doi.org/10.1016/j.mce.2005.10.003
State	Published - Dec 21 2005

Funding

We would like to acknowledge Dr. Eric Bremer for assistance with Affymetrix array hybridizations and the Northwestern University Center for Genetic Medicine for technical assistance with the cDNA microarray experiments. MDA-MB231 breast carcinoma cells were a gift from Dr. V. Craig Jordan, (Robert H. Lurie Cancer Center at Northwestern University Feinberg School of Medicine, Chicago, IL). Low density microarrays were printed by the Microarray Platform of The Prostate Centre at Vancouver General Hospital through the Pacific Northwest Prostate Cancer SPORE. This research was funded by NIH grants PO1 HD21921 (JLJ, JW), T32 GM008061 (CGK), and a SPORE in Breast Cancer P50 CA89018 (JLJ, JW, EJL).

Keywords

Estrogen receptor alpha
Microarray (human breast tumor)
Nonclassical
SERM

ASJC Scopus subject areas

Endocrinology
Molecular Biology
Biochemistry

UN SDGs

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

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10.1016/j.mce.2005.10.003

Cite this

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title = "ERE-independent ERα target genes differentially expressed in human breast tumors",

abstract = "The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERα can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-κB) at their cognate sites on DNA. We previously generated a mutant form of ERα (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERα into MDA-MB231 ERα-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17β-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERα pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERα responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERα pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERα target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.",

keywords = "Estrogen receptor alpha, Microarray (human breast tumor), Nonclassical, SERM",

author = "Christine Glidewell-Kenney and Jeffrey Weiss and Lee, {Eun Jig} and Suresh Pillai and Toshio Ishikawa and Ariazi, {Eric A.} and Jameson, {J. Larry}",

note = "Funding Information: We would like to acknowledge Dr. Eric Bremer for assistance with Affymetrix array hybridizations and the Northwestern University Center for Genetic Medicine for technical assistance with the cDNA microarray experiments. MDA-MB231 breast carcinoma cells were a gift from Dr. V. Craig Jordan, (Robert H. Lurie Cancer Center at Northwestern University Feinberg School of Medicine, Chicago, IL). Low density microarrays were printed by the Microarray Platform of The Prostate Centre at Vancouver General Hospital through the Pacific Northwest Prostate Cancer SPORE. This research was funded by NIH grants PO1 HD21921 (JLJ, JW), T32 GM008061 (CGK), and a SPORE in Breast Cancer P50 CA89018 (JLJ, JW, EJL). ",

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doi = "10.1016/j.mce.2005.10.003",

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T1 - ERE-independent ERα target genes differentially expressed in human breast tumors

AU - Glidewell-Kenney, Christine

AU - Weiss, Jeffrey

AU - Lee, Eun Jig

AU - Pillai, Suresh

AU - Ishikawa, Toshio

AU - Ariazi, Eric A.

AU - Jameson, J. Larry

N1 - Funding Information: We would like to acknowledge Dr. Eric Bremer for assistance with Affymetrix array hybridizations and the Northwestern University Center for Genetic Medicine for technical assistance with the cDNA microarray experiments. MDA-MB231 breast carcinoma cells were a gift from Dr. V. Craig Jordan, (Robert H. Lurie Cancer Center at Northwestern University Feinberg School of Medicine, Chicago, IL). Low density microarrays were printed by the Microarray Platform of The Prostate Centre at Vancouver General Hospital through the Pacific Northwest Prostate Cancer SPORE. This research was funded by NIH grants PO1 HD21921 (JLJ, JW), T32 GM008061 (CGK), and a SPORE in Breast Cancer P50 CA89018 (JLJ, JW, EJL).

PY - 2005/12/21

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N2 - The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERα can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-κB) at their cognate sites on DNA. We previously generated a mutant form of ERα (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERα into MDA-MB231 ERα-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17β-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERα pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERα responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERα pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERα target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.

AB - The classical pathway for estrogen receptor (ER) signaling is mediated by ER binding to an estrogen response element (ERE) in DNA. ERα can also act via a nonclassical pathway by altering the activities of other transcription factors (e.g., Sp1, AP-1, or NF-κB) at their cognate sites on DNA. We previously generated a mutant form of ERα (E207A/G208A) that does not bind to EREs, and therefore lacks signaling via the classical pathway but retains signaling via the nonclassical pathway. In the current study, we introduce this mutant ERα into MDA-MB231 ERα-negative breast carcinoma cells to identify nonclassical pathway genes that respond to 17β-estradiol (E2), selective estrogen receptor modulators (SERMs) tamoxifen (TAM) or raloxifene (RAL), or the estrogen antagonist ICI 182,780 (ICI). Consistent with a role for nonclassical signaling in SERM action, microarray analyses identify 268 responsive nonclassical ERα pathway target genes. ICI elicits the largest number of nonclassical genes, followed by RAL, TAM, and E2. Custom microarrays containing identified nonclassical ERα responsive genes are used to compare gene expression in human breast tumor (n = 34) and normal mammary epithelial cell (n = 9) samples. A subset of nonclassical genes (n = 32) are differentially expressed in breast tumors. In summary, we show that nonclassical ERα pathway target genes exhibit a range of transcriptional responses to SERMs and identify targets of this pathway as potentially relevant to breast cancer. The identification of nonclassical ERα target genes offers new insight into estrogen receptor signaling and cross talk with pathways that mediate breast tumor response to SERM therapy.

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ER -

ERE-independent ERα target genes differentially expressed in human breast tumors

Abstract

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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