ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer

Yoshiya Horimoto, Johan Hartman, Julie Millour, Steven Pollock, Yolanda Olmos, Ka-Kei Ho, R Charles Coombes, Matti Poutanen, Sari I Mäkelä, Mona El-Bahrawy, Valerie Speirs, Eric W-F Lam (Corresponding Author)

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.

Original languageEnglish
Pages (from-to)1148-1156
Number of pages9
JournalAmerican Journal of Pathology
Volume179
Issue number3
Early online date16 Jul 2011
DOIs
Publication statusPublished - Sep 2011

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Estrogen Receptors
Cell Proliferation
Breast Neoplasms
Messenger RNA
Cell Line
Estrogen Receptor alpha
Chromatin Immunoprecipitation
MCF-7 Cells
Response Elements
Growth
Reporter Genes
Heterografts
Genetic Promoter Regions
Nude Mice
Estrogens
Neoplasms
Proteins

Keywords

  • Animals
  • Breast Neoplasms
  • Cell Line, Tumor
  • Cell Proliferation
  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Female
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Humans
  • Immunohistochemistry
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • RNA, Messenger
  • Transcription, Genetic
  • Transplantation, Heterologous
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Horimoto, Y., Hartman, J., Millour, J., Pollock, S., Olmos, Y., Ho, K-K., ... Lam, E. W-F. (2011). ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer. American Journal of Pathology, 179(3), 1148-1156. https://doi.org/10.1016/j.ajpath.2011.05.052

ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer. / Horimoto, Yoshiya; Hartman, Johan; Millour, Julie; Pollock, Steven; Olmos, Yolanda; Ho, Ka-Kei; Coombes, R Charles; Poutanen, Matti; Mäkelä, Sari I; El-Bahrawy, Mona; Speirs, Valerie; Lam, Eric W-F (Corresponding Author).

In: American Journal of Pathology, Vol. 179, No. 3, 09.2011, p. 1148-1156.

Research output: Contribution to journalArticle

Horimoto, Y, Hartman, J, Millour, J, Pollock, S, Olmos, Y, Ho, K-K, Coombes, RC, Poutanen, M, Mäkelä, SI, El-Bahrawy, M, Speirs, V & Lam, EW-F 2011, 'ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer', American Journal of Pathology, vol. 179, no. 3, pp. 1148-1156. https://doi.org/10.1016/j.ajpath.2011.05.052
Horimoto, Yoshiya ; Hartman, Johan ; Millour, Julie ; Pollock, Steven ; Olmos, Yolanda ; Ho, Ka-Kei ; Coombes, R Charles ; Poutanen, Matti ; Mäkelä, Sari I ; El-Bahrawy, Mona ; Speirs, Valerie ; Lam, Eric W-F. / ERβ1 represses FOXM1 expression through targeting ERα to control cell proliferation in breast cancer. In: American Journal of Pathology. 2011 ; Vol. 179, No. 3. pp. 1148-1156.
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abstract = "In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.",
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AU - Horimoto, Yoshiya

AU - Hartman, Johan

AU - Millour, Julie

AU - Pollock, Steven

AU - Olmos, Yolanda

AU - Ho, Ka-Kei

AU - Coombes, R Charles

AU - Poutanen, Matti

AU - Mäkelä, Sari I

AU - El-Bahrawy, Mona

AU - Speirs, Valerie

AU - Lam, Eric W-F

N1 - Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

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N2 - In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.

AB - In this study, we investigated the effects of ectopic estrogen receptor (ER)β1 expression in breast cancer cell lines and nude mice xenografts and observed that ERβ1 expression suppresses tumor growth and represses FOXM1 mRNA and protein expression in ERα-positive but not ERα-negative breast cancer cells. Furthermore, a significant inverse correlation exists between ERβ1 and FOXM1 expression at both protein and mRNA transcript levels in ERα-positive breast cancer patient samples. Ectopic ERβ1 expression resulted in decreased FOXM1 protein and mRNA expression only in ERα-positive but not ERα-negative breast carcinoma cell lines, suggesting that ERβ1 represses ERα-dependent FOXM1 transcription. Reporter gene assays showed that ERβ1 represses FOXM1 transcription through an estrogen-response element located within the proximal promoter region that is also targeted by ERα. The direct binding of ERβ1 to the FOXM1 promoter was confirmed by chromatin immunoprecipitation analysis, which also showed that ectopic expression of ERβ1 displaces ERα from the endogenous FOXM1 promoter. Forced expression of ERβ1 promoted growth suppression in MCF-7 cells, but the anti-proliferative effects of ERβ1 could be overridden by overexpression of FOXM1, indicating that FOXM1 is an important downstream target of ERβ1 signaling. Together, these findings define a key anti-proliferative role for ERβ1 in breast cancer development through negatively regulating FOXM1 expression.

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KW - Female

KW - Forkhead Box Protein M1

KW - Forkhead Transcription Factors

KW - Humans

KW - Immunohistochemistry

KW - Mice

KW - Mice, Nude

KW - Neoplasm Transplantation

KW - RNA, Messenger

KW - Transcription, Genetic

KW - Transplantation, Heterologous

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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DO - 10.1016/j.ajpath.2011.05.052

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VL - 179

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EP - 1156

JO - American Journal of Pathology

JF - American Journal of Pathology

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