A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells

Zhang, XianTian; Kang, Lianguo; Ding, Ling; Vranić, Semir; Gatalica, Zoran; Wang, Zhaoyi

doi:10.1038/onc.2010.458

Cited by 144 publications

(196 citation statements)

References 23 publications

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“…Yingchun Zhao, 1 Caishu Deng, 2 Weida Lu, 1 Jing Xiao, 1 Danjun Ma, 1 Mingxi Guo, 1 Robert R Recker, ER-α36 expression was detected in both ER-α66-positive and-negative breast cancer tumors (10,11). High levels of ER-α36 expression also are associated with tamoxifen resistance; breast cancer patients with tumors highly expressing ER-α36 benefit less from tamoxifen treatment (12).…”

Section: O L M E D 1 7 ( 1 1 -1 2 ) 1 2 3 3 -1 2 4 1 N O V E M B mentioning

confidence: 99%

let-7 MicroRNAs Induce Tamoxifen Sensitivity by Downregulation of Estrogen Receptor α Signaling in Breast Cancer

Zhao

Deng

et al. 2011

Mol Med

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MicroRNAs (miRNAs) play an important regulatory role in breast tumorigenesis. Previously, we found that let-7 miRNAs were downregulated significantly in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues. In this study, we further found that endogenous levels of let-7b and let-7i miRNAs are inversely correlated with levels of estrogen receptor (ER)-a36, a new variant of ER-α66, in the FFPE tissue set. Bioinformatic analysis suggested that ER-α36 may be another target of let-7 miRNAs. To test this hypothesis, cotransfection of let-7 mimics or inhibitors together with full-length or a fragment of ER-α36 3′UTR luciferase construct was performed, and we found that let-7b and let-7i mimics suppressed the activity of reporter gene significantly, which was enhanced remarkably by let-7b and let-7i inhibitors. Both mRNA and protein expression of ER-α36 were inhibited by let-7 mimics and enhanced by let-7 inhibitors. Furthermore, ER-α36 mediated nongenomic MAPK and Akt pathways were weakened by let-7b and let-7i mimics in triple negative breast cancer cell line MDA-MB-231. The reverse correlation between let-7 miRNAs and ER-α36 also exists in Tamoxifen (Tam)-resistant MCF7 cell line. Transfection of let-7 mimics to Tam-resistant MCF7 cells downregulated ER-α36 expression and enhanced the sensitivity of MCF7 cells to Tam in estrogen-free medium, which could be restored by overexpression of ER-α36 constructs without 3′UTR. Our results suggested a novel regulatory mechanism of let-7 miRNAs on ER-α36 mediated nongenomic estrogen signal pathways and Tam resistance.

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Section: O L M E D 1 7 ( 1 1 -1 2 ) 1 2 3 3 -1 2 4 1 N O V E M B mentioning

confidence: 99%

let-7 MicroRNAs Induce Tamoxifen Sensitivity by Downregulation of Estrogen Receptor α Signaling in Breast Cancer

Zhao

Deng

et al. 2011

Mol Med

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“…ER-α36 mediated mitogenic estrogen signaling in ER-negative breast cancer cells, such as MDA-MB-231 and MDA-MB-436 cells that lack expression of ER-α66 but highly express ER-α36. It was reported that E 2 β induced the MAPK/ERK activation through a mechanism that involves ER-α36 and the EGFR/Src/Shc complex and exhibited a potent mitogenic estrogen signaling in vitro and in vivo [11,12,14]. …”

Section: Discussionmentioning

confidence: 99%

“…ERα-36 was expressed in ER-negative tumor samples and ER-negative breast cancer cell lines [14]. Some studies have suggested that ERα-36 is involved in nongenomic estrogen signaling, and ERα-36 promotes cell proliferation via the MAPK/ERK pathway in ER-negative breast cancers [13,14]. …”

Section: Introductionmentioning

confidence: 99%

“…Recently, a 36-kDa variant of ERα-66, named ER-a36 has been identified, it is mainly expressed in the cytoplasm and plasma membrane and has minimal or no nuclear expression in breast cancer cells [11,12,13]. ERα-36 was expressed in ER-negative tumor samples and ER-negative breast cancer cell lines [14]. Some studies have suggested that ERα-36 is involved in nongenomic estrogen signaling, and ERα-36 promotes cell proliferation via the MAPK/ERK pathway in ER-negative breast cancers [13,14].…”

Section: Introductionmentioning

confidence: 99%

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Increased Expression of Estrogen Receptor a-36 by Breast Cancer Oncogene IKKe Promotes Growth of ER-Negative Breast Cancer Cells

Sun

Zou

et al. 2013

Cell Physiol Biochem

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Background/Aims: The expression of estrogen receptor-α (ERα) is one of the most important diagnostic and prognostic factors of breast cancer. Recently, ERα-36 has been identified as a novel variant of ER-α. ERα-36 lacks intrinsic transcription activity and mainly mediates non-genomic estrogen signaling. The noncanonical IKK family member IKKε is essential for regulating antiviral signaling pathways and is recently discovered as a breast cancer oncogene. IKKε interacts with and phosphorylates ERα on serine 167, induces ERα transactivation activity and enhances ERα binding to DNA in ER-positive breast cancer cells. However, the correlation between IKKε and the ERα-36 signaling pathway in ER-negative breast cancer cells remains unclear. Methods and Results: In this study, we show that IKKε interacts with ERα-36 and increases its expression in breast cancer cells. As shown by western blot assays, the upregulation of ERα-36 by IKKε was significant. In MDA-MB-231 cells which are ER-negative, IKKε was able to increase the expression of ERα-36 in a dose-dependent manner, and the RNA interference assay indicated the correlation between IKKε and ERα-36 expression. Moreover, IKKε enhanced the growth of MDA-MB-231 and MDA-MB-436 cells. Conclusions: These results suggest that IKKε increases ERα-36 expression and is involved in ERα-36 mediated non-genomic estrogen signaling.

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“…One study depicts a novel cross-talk mechanism in which Advances in Breast Cancer Research EGFR and ERα36 positively regulate each other in TNBC, however ERα36 may dynamically change its partners during estrogen signaling in regards to EGFR and Src/Shc [163]. A mechanism for GPER has also been speculated.…”

Section: Localization Of Estrogen Receptor Is Significant In Breast Cmentioning

confidence: 99%

Role of ESR Pathway Genes in Breast Cancer: A Review

Kumar¹,

Myers²,

Homsi³

et al. 2018

ABCR

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Breast cancer is the leading cause of death in women. Prognosis of breast cancer is often pessimistic because the tumors are prone to metastasizing to the bone, brain, and lung. The estrogen signaling receptor (ESR) pathway contains 39 main genes and proteins which makes it one of the larger signaling pathways. Predominately this pathway and the proteins within are involved in breast growth and development, making it a prospective area of study for breast cancer. While the healthy ESR pathway has been constructed and is well established, a mechanistic model of mutated genes of ESR pathway has not been delved upon. Such mutated models could be utilized for selecting combinational targets for drug therapies, as well as elucidating crosstalk between other pathways and feedback mechanisms. To construct the mutated models of the ESR pathway it is imperative to assess what is currently understood in the literature and what inconsistencies exist in order to resolve them. Without this information, a model of the ESR pathway will be unreliable and likely unproductive. This review is the detailed literature survey of the biological studies performed on ESR pathways genes, and their respective roles in breast cancer. Furthermore, the details mentioned in the review can be beneficial for the integrated study of the ESR pathway genes, which includes, structural and dynamics study of the genes products, to have a holistic understanding of the cancer mechanism.

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A positive feedback loop of ER-α36/EGFR promotes malignant growth of ER-negative breast cancer cells

Cited by 144 publications

References 23 publications

let-7 MicroRNAs Induce Tamoxifen Sensitivity by Downregulation of Estrogen Receptor α Signaling in Breast Cancer

let-7 MicroRNAs Induce Tamoxifen Sensitivity by Downregulation of Estrogen Receptor α Signaling in Breast Cancer

Increased Expression of Estrogen Receptor a-36 by Breast Cancer Oncogene IKKe Promotes Growth of ER-Negative Breast Cancer Cells

Role of ESR Pathway Genes in Breast Cancer: A Review

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