Coregulation of estrogen receptor by ERBB4/HER4 establishes a growth-promoting autocrine signal in breast tumor cells.

Full Abstract

Although crosstalk between cell-surface and nuclear receptor signaling pathways has been implicated in the development and progression of endocrine-regulated cancers, evidence of direct coupling of these signaling pathways has remained elusive. Here we show that estrogen promotes an association between extranuclear estrogen receptor alpha (ER) and the epidermal growth factor receptor (EGFR) family member ERBB4. Ectopically expressed as well as endogenous ERBB4 interacts with and potentiates ER transactivation, indicating that the ERBB4/ER interaction is functional. Estrogen induces nuclear translocation of the proteolytic processed ERBB4 intracellular domain (4ICD) and nuclear translocation of 4ICD requires functional ligand-bound ER. The nuclear ER/4ICD complex is selectively recruited to estrogen-inducible gene promoters such as progesterone receptor (PgR) and stromal cell-derived factor 1 (SDF-1) but not to trefoil factor 1 precursor (pS2). Consistent with 4ICD-selective promoter binding, suppression of ERBB4 expression by interfering RNA shows that 4ICD coactivates ER transcription at the PgR and SDF-1 but not the pS2 promoter. Significantly, ERBB4 itself is an estrogen-inducible gene and the ERBB4 promoter harbors a consensus estrogen response element (ERE) half-site with overlapping activator protein-1 elements that bind ER and 4ICD in response to estrogen. Using a cell proliferation assay and a small interfering RNA approach, we show that ERBB4 expression is required for the growth-promoting action of estrogen in the T47D breast cancer cell line. Our results indicate that ERBB4 is a unique coregulator of ER, directly coupling extranuclear and nuclear estrogen actions in breast cancer. We propose that the contribution of an autocrine ERBB4/ER signaling pathway to tumor growth and therapeutic response should be considered when managing patients with ER-positive breast cancer.

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Author information

Author/s: Zhu, Yun (Y); Sullivan, Lacey L (LL); Nair, Sujit S (SS); Williams, Christopher C (CC); Pandey, Arvind K (AK); Marrero, Luis (L); Vadlamudi, Ratna K (RK); Jones, Frank E (FE);

Affiliation: Department of Biochemistry, Tulane University Health Sciences Center, Tulane Cancer Center, New Orleans, LA 70112-2699, USA.

Grants: R01CA95783 (Agency:NCI NIH HHS) ; R01CA96717 (Agency:NCI NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Cancer research (Cancer Res), published in United States. (Language: eng)

Reference: 2006-Aug; vol 66 (issue 16) : pp 7991-8

Dates: Created 2006/08/16; Completed 2007/11/13; Revised 2007/12/03;

PMID: 16912174, status: MEDLINE (last retrieval date: 12/26/2008)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Breast Neoplasms - pathology; physiopathology
Cell Division
Cell Line, Tumor
Cell Membrane - physiology
Cell Nucleus - physiology
Chromatin - genetics
Female

Gene Expression Regulation, Neoplastic
Homeostasis
Humans
Receptor Cross-Talk - physiology
Receptor, Epidermal Growth Factor - genetics; physiology
Receptors, Estrogen - genetics; physiology
Reverse Transcriptase Polymerase Chain Reaction

Associated Chemicals: Chromatin (0) ; Receptors, Estrogen (0) ; ERBB4 protein (EC 2.7.1.112) ; Receptor, Epidermal Growth Factor (EC 2.7.1.112)

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