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

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.

Keywords: ER; ER-α36; breast cancer; endocrine therapy resistance.

Figure 1

Structure of ER-α66 and ER-α36. Notes: (A) Transcription of ER-α36 initiates from a previously unidentified promoter in the first intron of ER-α66. We labeled the first exon of ER-α36 as “1” to distinguish it. Besides, ER-α36 has an extra, unique 27-amino-acid sequence at C-terminus which may broaden ligand-binding spectrum of ER-α36. (B) Compared to the protein structure of ER-α66, ER-α36 lacks both transactivation domains of AF-1 and AF-2 and retains DBD, Hinge, and LBD of ER-α66. Therefore, ER-α36 functions as a powerful competitor of ER-α66. Abbreviations: AF-1, activation function 1; AF-2, activation function 2; DBD, DNA binding domain; ER-α36, estrogen receptor-alpha36; ER-α66, estrogen receptor-alpha66; LBD, ligand binding domain.

Figure 2

Genomic and non-genomic activities mediated by ERs. Notes: ER-α66 binds to estrogen and then transfers to the nucleus to interact with specific EREs and induce transcription of target genes. ER-α36 has a broader ligand-binding spectrum than ER-α66 so that it can respond to E2α, E2β, E3, E4, and even tamoxifen. ER-α36 can mediate rapid MIES such as MAPK/ERK, PI3K/Akt, and PKC δ to regulate biological functions of cells. Abbreviations: Akt, protein kinase B; BCSCs, breast cancer stem cells; cdk 4, cyclin-dependent kinase 4; ER-α36, estrogen receptor-alpha36; ER-α66, estrogen receptor-alpha66; EREs, estrogen response elements; ERK, extracellular signal-regulated kinase; ERs, estrogen receptors; GSK3 β, glycogen synthase kinase 3 beta; JNKs, c-Jun N-terminal kinases; MAPK, mitogen-activated protein kinases; MIES, membrane-initiated estrogen signaling; PKC δ, protein kinase C delta; PI3K, phosphatidylinositide 3-kinase.

Figure 3

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.

Figure 4

ER-α36 and tamoxifen resistance. Notes: ER-α36 is an important cause of tamoxifen resistance. On the one hand, it activates membrane-initiated signaling pathways, such as MAPK/ERK, PI3K/AKT, and Src/EGFR/STAT5 pathways, causing the agonist effect of tamoxifen. On the other hand, ER-α36 upregulates EGFR and downregulates ER-α66 switching growth status from estrogen-dependent to growth-factor-dependent. Therefore, ER-α36 leads to tamoxifen resistance. Abbreviations: Akt, protein kinase B; EGFR, epidermal growth factor receptor; ER-α36, estrogen receptor-alpha36; ER-α66, estrogen receptor-alpha66; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinases; MCF-7/TAM, tamoxifen-resistant MCF-7 cell line; PI3K, phosphatidylinositide 3-kinase; STAT5, signal transducer and activator of transcription 5.