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ER-α36: a novel biomarker and potential therapeutic target in breast cancer.

Su X, Xu X, Li G, Lin B, Cao J, Teng L - Onco Targets Ther (2014)

Bottom Line: It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66).ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway.Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.

ABSTRACT
Estrogen receptor-alpha36 (ER-α36) is a 36-kDa variant of estrogen receptor-alpha (ER-α) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66). ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-α66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues. Thus, dysregulation of ER-α36 is closely associated with plenty of diseases including cancers. ER-α36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-α36 in endocrine therapy resistance. Therefore, ER-α36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-α36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.

No MeSH data available.


Related in: MedlinePlus

Positive feedback loop between EGFR and ER-α36.Notes: A positive feedback loop has been confirmed that EGFR signaling activates transcription of ER-α36 through an AP-1-binding site in the promoter region of ER-α36. In turn, ER-α36 is able to stabilize EGFR protein and mediate MAPK/ERK and Src/EGFR/STAT5 pathways. In the Src/EGFR/STAT5 pathway, Src functions as a switch by phosphorylation to enhance proliferation and malignant properties of cancer.Abbreviations: AP-1, activator protein 1; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-alpha36; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; STAT5, signal transducer and activator of transcription 5.
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f3-ott-7-1525: Positive feedback loop between EGFR and ER-α36.Notes: A positive feedback loop has been confirmed that EGFR signaling activates transcription of ER-α36 through an AP-1-binding site in the promoter region of ER-α36. In turn, ER-α36 is able to stabilize EGFR protein and mediate MAPK/ERK and Src/EGFR/STAT5 pathways. In the Src/EGFR/STAT5 pathway, Src functions as a switch by phosphorylation to enhance proliferation and malignant properties of cancer.Abbreviations: AP-1, activator protein 1; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-alpha36; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; STAT5, signal transducer and activator of transcription 5.

Mentions: Many investigators discovered a significant co-expression of ER-α36 and epidermal growth factor receptor (EGFR) in primary breast cancers, indicating that ER-α36 took part in EGFR-related carcinogenesis.19 Further studies elucidated that epidermal growth factor (EGF) induced phosphorylation of ERK1/2 via ER-α36 in a time- and dose-dependent pattern.18 A positive feedback loop was confirmed that EGFR signaling activated transcription of ER-α36 through an activator-protein-1-binding site in the promoter of ER-α36. In turn, ER-α36 interacted with the EGFR/Src/Shc complex to strengthen the EGFR signaling pathway and stabilize EGFR protein (Figure 3).20 A similar feedback loop between ER-α36 and human epidermal growth factor receptor 2 (HER-2), a member of the EGFR family, was reported.53 Interestingly, our previous study found that HER-2 expression didn’t increase in tamoxifen-resistant cells, which overexpressed ER-α36 and EGFR.23 In the Src/EGFR/signal transducer and activator of transcription 5 (STAT5) pathway mediated by ER-α36, Src functions as a switch to adjust phosphorylation of EGFR and then recruits STAT5 as a downstream effector, which regulates activation of the MAPK/ERK signaling pathway and expression of cyclin D1 (Figure 3).16,20,54 Therefore, the positive feedback loops between ER-α36 and growth factor receptors are important for cellular function, although the definite mechanism has not been clarified.


ER-α36: a novel biomarker and potential therapeutic target in breast cancer.

Su X, Xu X, Li G, Lin B, Cao J, Teng L - Onco Targets Ther (2014)

Positive feedback loop between EGFR and ER-α36.Notes: A positive feedback loop has been confirmed that EGFR signaling activates transcription of ER-α36 through an AP-1-binding site in the promoter region of ER-α36. In turn, ER-α36 is able to stabilize EGFR protein and mediate MAPK/ERK and Src/EGFR/STAT5 pathways. In the Src/EGFR/STAT5 pathway, Src functions as a switch by phosphorylation to enhance proliferation and malignant properties of cancer.Abbreviations: AP-1, activator protein 1; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-alpha36; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; STAT5, signal transducer and activator of transcription 5.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4155893&req=5

f3-ott-7-1525: Positive feedback loop between EGFR and ER-α36.Notes: A positive feedback loop has been confirmed that EGFR signaling activates transcription of ER-α36 through an AP-1-binding site in the promoter region of ER-α36. In turn, ER-α36 is able to stabilize EGFR protein and mediate MAPK/ERK and Src/EGFR/STAT5 pathways. In the Src/EGFR/STAT5 pathway, Src functions as a switch by phosphorylation to enhance proliferation and malignant properties of cancer.Abbreviations: AP-1, activator protein 1; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-alpha36; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; STAT5, signal transducer and activator of transcription 5.
Mentions: Many investigators discovered a significant co-expression of ER-α36 and epidermal growth factor receptor (EGFR) in primary breast cancers, indicating that ER-α36 took part in EGFR-related carcinogenesis.19 Further studies elucidated that epidermal growth factor (EGF) induced phosphorylation of ERK1/2 via ER-α36 in a time- and dose-dependent pattern.18 A positive feedback loop was confirmed that EGFR signaling activated transcription of ER-α36 through an activator-protein-1-binding site in the promoter of ER-α36. In turn, ER-α36 interacted with the EGFR/Src/Shc complex to strengthen the EGFR signaling pathway and stabilize EGFR protein (Figure 3).20 A similar feedback loop between ER-α36 and human epidermal growth factor receptor 2 (HER-2), a member of the EGFR family, was reported.53 Interestingly, our previous study found that HER-2 expression didn’t increase in tamoxifen-resistant cells, which overexpressed ER-α36 and EGFR.23 In the Src/EGFR/signal transducer and activator of transcription 5 (STAT5) pathway mediated by ER-α36, Src functions as a switch to adjust phosphorylation of EGFR and then recruits STAT5 as a downstream effector, which regulates activation of the MAPK/ERK signaling pathway and expression of cyclin D1 (Figure 3).16,20,54 Therefore, the positive feedback loops between ER-α36 and growth factor receptors are important for cellular function, although the definite mechanism has not been clarified.

Bottom Line: It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66).ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway.Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgical Oncology, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, People's Republic of China.

ABSTRACT
Estrogen receptor-alpha36 (ER-α36) is a 36-kDa variant of estrogen receptor-alpha (ER-α) firstly identified and cloned by Wang et al in 2005. It lacks both transactivation domains (activation function 1 and activation function 2) and has different biological characteristics compared to traditional ER-α (ER-α66). ER-α36 primarily locates on plasma membrane and cytoplasm and functions as a mediator in the rapid membrane-initiated non-genomic signaling pathway. Additionally, it inhibits the traditional genomic signaling pathway mediated by ER-α66 in a dominant-negative pattern. Accumulating evidence has demonstrated that ER-α36 regulates the physiological function of various tissues. Thus, dysregulation of ER-α36 is closely associated with plenty of diseases including cancers. ER-α36 is recognized as a molecular abnormality which solidly correlates to carcinogenesis, aggressiveness, and therapeutic response of breast cancer. Additionally, special attention has been paid to the role of ER-α36 in endocrine therapy resistance. Therefore, ER-α36 provides a novel biomarker of great value for diagnosis, prognosis, and treatment of breast cancer. It may also be a potential therapeutic target for breast cancer patients, especially for those who are resistant to endocrine therapy. In this review, we will overview and update the biological characteristics, underlying mechanism, and function of ER-α36, focusing on its biological function in breast cancer and endocrine therapy resistance. We will evaluate its application value in clinical practice.

No MeSH data available.


Related in: MedlinePlus