Estrogen receptor DNA binding is not required for estrogen-induced breast cell growth

DeNardo, David G.; Cuba, Valerie L.; Kim, Hee Tae; Wu, Kendall; Lee, Adrian V.; Brown, Powel H.

doi:10.1016/j.mce.2007.07.006

Cited by 32 publications

(25 citation statements)

References 42 publications

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“…The growth promoting activity of 4ICD in this system appeared to be mediated by nuclear signaling activity [22]. The molecular basis of nuclear [52,53] the exact composition of coactivation complexes at these promoters will be an area of important future investigation. …”

mentioning

confidence: 83%

“…The laboratory of Powell Brown has made significant progress towards clarifying the molecular basis of estrogen regulation at AP-1 sites and his group has examined the consequences of suppressed estrogen stimulation of genes regulated by these promoters. To summarize the findings of his laboratory and others, estrogen stimulates ERα recruitment to AP-1 sites within target promoters, even in the absence of an obvious ERE [49][50][51][52], and surprisingly these AP-1 target genes harboring non-canonical ERα recruitment sequences, including cyclin D1 and cmyc, mediate estrogen induced proliferation of breast tumor cells [52,53]. Interestingly, ERα does not directly bind DNA at these sites but rather is thought to be part of a coactivator complex that is anchored by the c-Jun transcription factor [53].…”

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

“…To summarize the findings of his laboratory and others, estrogen stimulates ERα recruitment to AP-1 sites within target promoters, even in the absence of an obvious ERE [49][50][51][52], and surprisingly these AP-1 target genes harboring non-canonical ERα recruitment sequences, including cyclin D1 and cmyc, mediate estrogen induced proliferation of breast tumor cells [52,53]. Interestingly, ERα does not directly bind DNA at these sites but rather is thought to be part of a coactivator complex that is anchored by the c-Jun transcription factor [53]. Both suppression of HER4 expression and expression of a dominant negative c-Jun (Tam67) results in a significant but not complete loss of estrogen proliferative response in breast cancer cells [21,45,52].…”

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

“…It is therefore tempting to speculate that 4ICD is an important component of the growth promoting ERα coactivator complex at AP-1 sites in estrogen regulated genes. With AP-1 sites emerging as one of the predominant sequence elements involved in estrogen stimulated ERα recruitment [51] and estrogen stimulated proliferation of breast tumor cells [52,53] the exact composition of coactivation complexes at these promoters will be an area of important future investigation.…”

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

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HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Jones

2008

J Mammary Gland Biol Neoplasia

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The HER4 receptor tyrosine kinase was the final member of the EGFR-family to be discovered. In contrast to the other three members of this receptor family which function primarily as mitogenic effectors in the breast, HER4 appears to have multiple divergent functions in the normal and malignant breast. Interestingly, the majority of HER4 activities in the breast including pregnancy induced differentiation and lactation initiation, transcriptional activation, tumor cell proliferation, growth suppression, and induction of apoptosis appear to be mediated by an independently signaling soluble HER4 intracellular domain (4ICD). The 4ICD can accumulate within the nucleus or mitochondria and subcellular localization of 4ICD in part determines the physiological response of breast cells to 4ICD action. Here I will discuss the evidence supporting the role of 4ICD as the critical effector of HER4 signaling in the breast. In addition a developmental and temporal model of 4ICD action in the normal breast and during the progression of breast cancer will be presented to explain the paradox of divergent HER4 and 4ICD activities. KeywordsEGFR-family; Estrogen receptor; BCL-2 family; Apoptosis; Transcription Proteolytic Processing of HER4 to Generate a Soluble HER4 Intracellular Domain (4ICD)It is well accepted that the HER4 transmembrane receptor undergoes regulated intramembrane proteolysis (RIP) at the cell surface to release a soluble intracellular domain (ICD); a property that remains unique among EGFR-family members. An excellent review of the molecular details underlying HER4 RIP was recently published elsewhere [1]. In summary, ectodomain cleavage of the 180 kDa HER4 cell surface receptor is mediated by tumor necrosis factor α converting enzyme (TACE), a member of the ADAM metalloproteinase family referred to as ADAM17 [2]. Following TACE cleavage the ca. 120 kDa HER4 ectodomain, which includes the ligand binding region, is shed into the extracellular milieu while the remaining 80 kDa cleavage product (m80) is retained as a transmembrane peptide. The m80 harbors an active tyrosine kinase [3] and a carboxyl terminus with several potential tyrosine phosphorylation sites. Although the m80 is phosphorylated it remains unclear if this membrane tethered peptide transmits cellular signals. The HER4 m80 however is a substrate for presenilin-dependentsecretase cleavage. This RIP event results in membrane release of a soluble 4ICD. Depending upon specific cellular properties, that we are beginning to understand, membrane released 4ICD may translocate to the nucleus or remain in the cytosol where mitochondrial accumulation has e-mail: fjones@tulane.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript been observed (Fig. 1). The 4ICD is emerging as a unique independently signaling molecule and the impact of 4ICD signaling in the breast will be discussed in detail here. [16][17][18]. Although there is increasing evidence to suggest that phosphorylation of γ-secretase and its substra...

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mentioning

confidence: 83%

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

Section: Nuclear 4icd Functions As a Growth Promoting Estrogen Receptmentioning

confidence: 99%

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HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

Jones

2008

J Mammary Gland Biol Neoplasia

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“…The 4ICD fragment also functions as a selective ER co-activator since it regulates expression of PGR, SDF-1 and Erb-B4 itself. This involves ER recruitment not to canonical ERE sites but to AP-1 sites in a complex with c-Jun (DeNardo et al, 2007). In contrast, cytosolic 4ICD may have different functions, which may explain to breast cancer biology.…”

Section: Interactions Between Stromal Cells and Mammary Epithelial Cementioning

confidence: 99%

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Eccles¹

2011

Int. J. Dev. Biol.

159

123

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KEY WORDS: EGFR, c-Erb-B2, c-Erb-B3, c-Erb-B4, cancer The EGFR/ERB-B/HER familyThe epidermal growth factor receptor (EGFR) and its close relatives HER2/c-Erb-B2, Erb-B3 and Erb-B4 are type 1 transmembrane receptor tyrosine kinases (RTK) with key roles in embryonic development, tissue renewal/repair and cancer. A great deal has been learned about their structure, signalling pathways and aberrations linked to malignant transformation since the explosion of interest in this family in the 1980's. Early discoveriesregulated eyelid opening in mice, and as the binding partner for EGFR was found to have kinase activity when stimulated with ligands and to be capable of phosphorylating tyrosine residues on both itself and downstream targets. Even before EGFR was identiInt. J. Dev. Biol. 55: [685][686][687][688][689][690][691][692][693][694][695][696]

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Molecular mechanism of estrogen–estrogen receptor signaling

Yaşar

Ayaz

User

et al. 2016

Reprod Medicine & Biology

346

240

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Abstract17β‐Estradiol (E2), as the main circulating estrogen hormone, regulates many tissue and organ functions in physiology. The effects of E2 on cells are mediated by the transcription factors and estrogen receptor (ER)α and ERβ that are encoded by distinct genes. Localized at the peri‐membrane, mitochondria, and the nucleus of cells that are dependent on estrogen target tissues, the ERs share similar, as well as distinct, regulatory potentials. Different intracellular localizations of the ERs result in dynamically integrated and finely tuned E2 signaling cascades that orchestrate cellular growth, differentiation, and death. The deregulation of E2–ER signaling plays a critical role in the initiation and progression of target tissue malignancies. A better understanding of the complex regulatory mechanisms that underlie ER actions in response to E2 therefore holds a critical trajectory for the development of novel prognostic and therapeutic approaches with substantial impacts on the systemic management of target tissue diseases.

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Estrogen receptor DNA binding is not required for estrogen-induced breast cell growth

Cited by 32 publications

References 42 publications

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

HER4 Intracellular Domain (4ICD) Activity in the Developing Mammary Gland and Breast Cancer

The epidermal growth factor receptor/Erb-B/HER family in normal and malignant breast biology

Molecular mechanism of estrogen–estrogen receptor signaling

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