Gene: ESR2 maps to 14q22-24; size: about 40-kb. The ESR2 gene comprises 8 exons and 7introns.
mRNA: sizes: about 7-kb (major) and 9.5-kb. Northern blot analysis showed that ER-beta is expressed in human thymus, spleen, ovary, and testis.
Protein: The first human cDNA sequence published reported a length of 487 amino acids (Mosselman S. et al.,1996). Longer cDNA sequences were subsequently reported, predicting a primary translation product of 530 amino acid residues (Moore J.T. et al., 1998; Ogawa S. et al., 1998). ER-beta has high homology to
ER-alpha in the DNA- (97%) and ligand-binding (59%) domains, but encodes a distinct transcriptional activating function-1 (AF-1) domain. ER-beta may be transactivated by 17-beta-estradiol, and the antioestrogen ICI-164384 appears to be a potent antagonist for ER-beta. See also
Estrogen receptors alpha and beta, differences and similarities
Cell lines:
- ER-ß was expressed in chemically transformed human breast epithelial cells (Hu Y.F. et al., 1998).
- ER-ß was found in the
ER-alpha negative MDA-MB-231 breast cancer cells (BCC). A splice variant was also expresed by these cells (Vladusic E. et al., 1998).
- RT-PCR analysis showed that in T-47D BCC, ER-ß mRNA expression was reduced in a time- and dose-dependent manner by the progestins medroxyprogesterone acetate (MPA) and Org 2058, while dexamethasone was devoid of effect (Dotzlaw H. et al., 1999).
- Monoclonal antibodies were made against a peptide representing the first 18 amino acids of the longest ER-ß open reading frame reported, and polyclonal antibodies were made against a peptide within the ER-ß B domain. By western blot analysis, ER-ß protein was found in all BCC lines (MCF-7, MDA-MB-231, MDA-MB-435) tested. Shorter ER-ß isoforms were detected in the
ER-alpha negative MDA-MB-231 and MDA-MB-435 (Fuqua S.A.W. et al., 1999).
- Using RT-PCR, the expression of ER-ß mRNA was found greater in a tamoxifen-resistant MCF-7 clone than that observed in tamoxifen-sensitive MCF-7 (Speirs V. et al., 1999b).
Tumors:
- The expression of
ER-alpha and -beta mRNA was determined by RT-PCR in 23 normal and 60 malignant breast cancer tissues. The percentages of normal tissues expressing
ER-alpha alone, ER-beta alone,
ER-alpha and ER-beta, or no ER, were equal to 13%, 22%, 13%, and 52%, respectively. In malignant tissues, these values were equal to 27%, 0%, 50%, and 23%, respectively. Those tumours that coexpressed
ER-alpha and ER-beta were node positive (P=0.02; Fisher's exact test) and tended to be of higher grade (Speirs V. et al., 1999a).
- In a series of 40 breast tumors, the level of ER-ß mRNA, determined by RT-PCR, was assessed according to either ER status or
PgR status, determined by ligand binding assays. ER-beta mRNA level was was significantly lower in
PgR+ tumors compared with
PgR- tumors (P=0.036), and no association with ER status was found. Subgroup analysis showed that ER-beta mRNA expression in ER+/
PgR+ breast tumors was significantly less than in ER+/
PgR- (P=0.009), ER-/
PgR+ (P=0.029), and ER-/
PgR- (P=0.023) groups (Dotzlaw H. et al., 1999).
- The expression of ER-ß was studied in 25 cases of invasive ductal carcinoma of the breast, using in situ hybridization, and the findings were compared with those of
ER-alpha.
ER-alpha and ER-beta hybridization signals were both detected, predominantly in carcinoma cells and in some stromal cells, in 18 of 25 (72%) and 11 of 25 (44%) cases, respectively. The cases in which more than 25% of carcinoma cells demonstrated mRNA hybridization signals were 13 of 25 (52%) and 2 of 25 (8%) cases for
ER-alpha and ER-beta, respectively. Among the cases expressing ER-beta, 10 of 11 (91%) also expressed
ER-alpha mRNA; and in these 10 cases, coexpressing both
ER-alpha and beta, the number of carcinoma cells expressing
ER-alpha was greater than that expressing ER-beta in 9 cases. Eight cases demonstrated only
ER-alpha mRNA hybridization signals in carcinoma cells. These results indicate that ER-beta is coexpressed with
ER-alpha in most ER-beta-positive breast carcinoma cells, which suggests that the expression of ER-beta depends on the presence of
ER-alpha in the great majority of human breast cancer (Sasano H. et al., 1999).
- Using RT-PCR, the relative expression of mRNA for both ER-ß and transforming growth factor ß1 (TGF-ß1) was determined in two group of breast cancer patients, a tamoxifen-sensitive group (n=8) and a tamoxifen-resistant group (n=9). ER-ß mRNA was significantly up-regulated in the tamoxifen-resistant group as compared with the tamoxifen-sensitive group, and, consistent with previous findings, TGF-ß1 was also up-regulated in the tamoxifen-resistant cohort (Speirs V. et al., 1999b).
- Monoclonal antibodies were made against a peptide representing the first 18 amino acids of the longest ER-ß open reading frame reported, and polyclonal antibodies were made against a peptide within the ER-ß B domain. By western blot analysis, ER-ß protein was found in three of five breast tumor samples (Fuqua S.A.W. et al., 1999).
Dotzlaw H. et al. (1997) Expression of estrogen receptor-beta in human breast tumors. J. Clin. Endocrinol. Metab. 82, 2371-2374.
Dotzlaw H. et al. (1999) Estrogen receptor-beta messenger RNA expression in human breast tumor biopsies: relationship to steroid receptor status and regulation by progestins. Cancer Res. 59, 529-532.
Enmark E. et al. (1997) Human estrogen receptor ß-gene structure, chromosomal localization, and expression pattern. Endocrinology 82, 4258-4265.
Fuqua S.A.W. et al. (1999) Expression of wild-type estrogen receptor ß and variant isoforms in human breast cancer. Cancer Res. 59, 5425-5428.
Hu Y.F. et al. (1998) Increased expression of estrogen receptor ß in chemically transformed human breast epithelial cells. Int. J. Oncol. 12, 1225-1228.
Kuiper G.G.J.M. et al. (1997) A comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta. Endocrinology 138, 863-870.
Lu B. et al. (1998) Estrogen receptor-beta mRNA variants in human and murine tissues. Mol. Cell. Endocrinol. 138, 199-203.
Moore J. et al. (1998) Cloning and characterization of human estrogen receptor ß isoforms. Biochem. Biophys. Res. Commun. 247, 75-78.
Mosselman S. et al. (1996) ERß: identification and characterization of a novel human estrogen receptor. FEBS Lett. 392, 49-53.
Ogawa S. et al. (1998) Molecular cloning and characterization of human estrogen receptor betacx: a potential inhibitor of estrogen action in human. Nucleic Acids Res. 26, 3505-3512.
Paech K. et al. (1997) Differential ligand activation of estrogen receptors ERalpha and ERbeta at AP-1 sites. Science 277, 1508-1510.
Sasano H. et al. (1999) Messenger ribonucleic acid in situ hybridization analysis of estrogen receptors alpha and beta in human breast carcinoma. J. Clin. Endocrinol. Metab. 84, 781-785.
Speirs V. et al. (1999a) Coexpression of estrogen receptor
alpha and beta: poor prognostic factors in human breast cancer? Cancer Res. 59, 525-528.
Speirs V. et al. (1999b) Increased expression of estrogen receptor ß mRNA in tamoxifen-resistant breast cancer patients. Cancer Res. 59, 5421-5424.
Vladusic E. et al. (1998) Expression of estrogen receptor beta messenger RNA variant in breast cancer. Cancer Res. 58, 210-214.
