The Isoforms of Estrogen Receptor Alpha and Beta in Thyroid Cancer (original) (raw)
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Expression of thyroid hormone receptor/erbA genes is altered in human breast cancer
Oncogene, 2002
The relation between thyroid status and diseases and cancer is unclear. No detailed analysis of thyroid hormone receptor (TR) expression in human breast cancer has been reported. We have analysed the expression and mutational status of the TRa1, encoded by the c-erbA proto-oncogene, TRb1 and TRb2 isoforms in 70 sporadic breast cancers. Alterations in the RNA level of TRb1, TRa1, or both were found in a number of patients. No expression of TRb2 RNA was detected. Western blotting analysis con®rmed the dierences in expression at the protein level in those cases where sucient tumor sample was available. Additionally, tumor-speci®c truncated TRb1 RNA was found in six patients. Strikingly, three transcripts shared the same breakpoint. Only one tumor carried the corresponding deletion at the genomic DNA level, suggesting that the remaining abnormal TRb1 transcripts are aberrant splicing products. Though no signi®cant correlation was found between TRb1 alteration and any clinical parameter, it showed a tendency to associate with early age of onset (550 years). Our results reveal speci®c alterations in the expression of TRb and TRa genes in a subset of breast cancer patients, suggesting that deregulation of thyroid hormone target genes may be involved in the generation of this neoplasia.
International Journal of Molecular Sciences, 2022
Papillary thyroid carcinomas (PTC), which is derived from thyroid follicular cells, is the most commonly differentiated thyroid cancer with sex disparity. However, the role of estrogen receptors (ERs) in the pathogenesis of PTC remains unclear. The present study aimed to determine the association of ER mRNA expression levels with clinicopathologic features in PTC. To that aim, the mRNA levels of ESR1 (ERα66), ESR1 (ERα36), ESR2, and G-protein-coupled estrogen receptor 1 (GPER1) in snap-frozen tissue samples from PTCs and adjacent normal thyroid tissues were determined using quantitative reverse transcription polymerase chain reaction (RT-qPCR), and the correlation between ER mRNA expression levels and clinicopathologic features was analyzed. The expression of ERα66, ERα36, ERβ, and GPER1 was lower in PTC specimens than in adjacent normal thyroid tissues. Moreover, low GPER1 expression was associated with extrathyroidal extension. There was no obvious difference in expression of ERs ...
Estrogen receptor beta impacts hormone-induced alternative mRNA splicing in breast cancer cells
BMC Genomics, 2015
Background: Estrogens play an important role in breast cancer (BC) development and progression; when the two isoforms of the estrogen receptor (ERα and ERβ) are co-expressed each of them mediate specific effects of these hormones in BC cells. ERβ has been suggested to exert an antagonist role toward the oncogenic activities of ERα, and for this reason it is considered an oncosuppressor. As clinical evidence regarding a prognostic role for this receptor subtype in hormone-responsive BC is still limited and conflicting, more knowledge is required on the biological functions of ERβ in cancer cells. We have previously described the ERβ and ERα interactomes from BC cells, identifying specific and distinct patterns of protein interactions for the two receptors. In particular, we identified factors involved in mRNA splicing and maturation as important components of both ERα and ERβ pathways. Guided by these findings, here we performed RNA sequencing to investigate in depth the differences in the early transcriptional events and RNA splicing patterns induced by estradiol in cells expressing ERα alone or ERα and ERβ. Results: Exon skipping was the most abundant splicing event in the post-transcriptional regulation by estradiol. We identified several splicing events induced by ERα alone and by ERα + ERβ, demonstrating for the first time that ERβ significantly affects estrogen-induced splicing in BC cells, as revealed by modification of a subset of ERα-dependent splicing by ERβ, as well as by the presence of splicing isoforms only in ERβ + cells. In particular, we observed that ERβ + BC cell lines exhibited around 2-fold more splicing events than the ERβ-cells. Interestingly, we identified putative direct targets of ERβ-mediated alternative splicing by correlating the genomic locations of ERβ and ERα binding sites with estradiol-induced differential splicing in the corresponding genes. Conclusions: Taken together, these results demonstrate that ERβ significantly affects estrogen-induced early transcription and mRNA splicing in hormone-responsive BC cells, providing novel information on the biological role of ERβ in these tumors.
International Journal of Oncology, 2010
Premenopausal women are at highest risk for papillary and follicular thyroid carcinoma, implicating a role for estrogens in thyroid cancer. The expression of estrogen receptors • and ß (ER), the effects of estradiol (E 2), selective estrogen receptor modulators (SERMs) 4-hydroxytamoxifen and raloxifene, and ER subtype selective agonists were examined in NPA87 and KAT5 papillary and WRO follicular thyroid carcinoma cell lines. All three thyroid cancer cell lines expressed full-length ER• and ERß proteins with cytoplasmic localization that was unaffected by E 2. ICI 182,780 (Fulvestrant, an ER antagonist), and inhibitors of non-genomic E 2-activated MAPK and PI3K signaling blocked E 2-induced cell proliferation. SERMs acted in a cell line-specific manner. No E 2-induced estrogen response element (ERE)-driven reporter activity was observed in transiently transfected thyroid cancer cells. However, E 2 increased transcription of established endogenous E 2-target genes, i.e., cathepsin D in WRO and cyclin D1 in both KAT5 and WRO cells in an ER-dependent manner as validated by inhibitor and siRNA experiments. In contrast, E 2 did not increase progesterone receptor expression in the thyroid cancer cell lines. E 2 stimulated phosphorylation of ERK1/2 in KAT5 and WRO cells and siER• or siERß inhibited E 2-induced ERK phosphorylation. Expression of the putative membrane estrogen receptor GPR30 was detected in WRO, but not NPA87 or KAT5 cells. GPR30 expression was lower in WRO than MCF-7 human breast cancer cells. Overall, these findings suggest E 2-mediated thyroid cancer cell proliferation involves ER• and ERß transcriptional and non-genomic signaling events.
Endocrine Related Cancer, 2012
Estrogen receptor (ER) and androgen receptor (AR) may be expressed in thyroid tumors, but their prognostic role is controversial. We investigated whether ER and AR expressions could confer a more aggressive phenotype to thyroid tumors. We enrolled 91 patients (13 males and 78 females, mean age 49.3±14.8 years) bearing small (T1 in the 2006 TNM system) differentiated thyroid cancers (DTC). Thirty-eight tumors were incidental histological findings. Using immunohistochemistry, we evaluated ERα, ERβ, and AR expressions in tumors and in its correspondent extra-tumor parenchyma. In tumors, 13 (16.7%) women and one (7.7%) man expressed ERα; 42 (53.8%) women and six (46%) men expressed ERβ; and 16 (20.5%) women and three (23.1%) men expressed AR. In normal thyroid parenchymas, ERβ was expressed in 52 (66.7%) women and nine (69.2%) men, ERα in three (3.8%) women, and AR in 13 (16.7%) women. Compared with normal thyroid parenchyma, tumors gained ERα and lost ERβ expressions. Incidental cancer...
The Journal of steroid biochemistry and molecular biology, 2006
A novel estrogen receptor-related protein (ERR) gamma splice variant cDNA (ERRgamma3) was found in human full-length cDNA libraries. ERRgamma3 cDNA consists of 3362 base pairs and has an open reading frame of 1188bp. The predicted peptide sequence of ERRgamma3 differs from both ERRgamma1 and ERRgamma2 in missing 39 amino acid residues corresponding to the second zinc finger motif of the DNA binding domain (DBD). ERRgamma3 gene consists of 8 exons including three unique 5'-terminal exons and lacks the exon encoding the second zinc finger motif. The expression of ERRgamma3 was confined to adipocytes and prostate while that of ERRgamma2 was fairly widespread. The ERRgamma3 product was shown by transactivation assay to have no ability to activate ERE-controlled transcription. However, ERRgamma3 has an ability to modulate the transcriptional activity of other nuclear hormone receptors. ERRgamma3 augmented the ligand-dependent transcriptional activities of ER (estrogen receptor) alpha...
Identification of candidates for tumor-specific alternative splicing in the thyroid
Genes, Chromosomes and Cancer, 2006
Alternative splicing is the differential processing of exon junctions to produce a new transcript variant from one gene. Some aberrant splicing, however, has been shown to be cancer specific. Identification of these specific splice variations will provide important insight into the molecular mechanism of normal cellular physiology as well as the disease processes. To gain knowledge about whether alternative splicing is linked to thyroid tumorigenesis, we used our prediction database to select targets for analysis. Fifteen putatively new alternative splicing isoforms were selected on the basis of their expression in thyroid libraries and/or their origin in genes previously associated with carcinogenesis. Using a set of 66 normal, benign, and malignant thyroid tissue samples, new splicing events were confirmed by RT-PCR for 13 of 15 genes (a validation rate of 87%). In addition, new alternative splicing isoforms not predicted by the system and not previously described in public databases were identified. Five genes (PTPN18, ABI3BP, PFDN5, SULF2, and ST5) presented new and/or additional unpredicted isoforms differentially expressed between malignant and benign or normal thyroid tissues, confirmed by sequencing. PTPN18, ABI3BP, and PFDN5 revealed a statistically significant differential splicing profile. In addition, real-time PCR analysis revealed that expression of an alternative PFDN5 variant was higher in malignant lesions than in benign lesions or normal tissues.
Estrogen and estrogen receptors in thyroid carcinomas
Journal of Surgical Oncology, 1991
Thyroid tissues, composed of normal thyroid (10 cases), Graves' thyroid (4), and papillary carcinoma (lo), were measured for the presence of receptors for estrogen (ER) using an enzyme-immunoassay method. The mean value of ER in papillary carcinoma tissues (4.0 ? 3.6 fmol/mg protein) was higher than that in normal thyroid tissues (0.8 -+ 0.4 fmol/mg protein) or that in Graves' thyroids (2.6 ? 0.9 fmol/mg protein). In 10 papillary carcinomas, 3 were from male patients and 7 were from females. The mean value of ER in the tumors from male patients (7.2 2 5.1 fmol/mg protein) was higher than that from female patients (2.6 -+ 1.7 fmol/mg protein).