Encoding Estrogen Receptor Alpha Research Articles

Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer

Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor-expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.

Estrogen receptor 1 polymorphisms are associated with airway hyperresponsiveness and lung function decline, particularly in female subjects with asthma

Sex hormones may contribute to the higher prevalence and severity of adult asthma in women compared with men. Sequence variants in the estrogen receptor alpha gene (ESR1) may alter estrogen action in asthma. Two hundred asthma probands and their families (n=1249) were genotyped for 5 single nucleotide polymorphisms (SNPs) in the ESR1 gene (intervening sequence 1 [IVS1]-1505A/G, IVS1-1415T/C, IVS1-397C/T, IVS1-351G/A and exon1+30T/C). Association with asthma and bronchial hyperresponsiveness (BHR) were tested. In the asthma probands, association of SNPs with BHR severity and annual FEV1 decline were determined. No SNP was associated with asthma. IVS1-397 was significantly associated with the presence of BHR (P=.02) and interacted with sex; female subjects with the CT or TT genotype were at risk (P=.01). In asthma probands, all SNPs were associated with FEV1 decline. Exon1+30 CT and TT group had an excess decline of 11.6 mL/y (P=.03) and 15.7 mL/y (P=.01), respectively, compared with the CC group. Of the IVS1 polymorphisms, IVS1-351G/A showed the strongest association, with the AA group having excess decline of 16.1 mL/y (P=.01) compared with the GG group. In subanalyses by sex, these associations were significant only in female subjects. ESR1 gene variants may affect development of BHR, particularly in female subjects. They may also lead to a more rapid lung function loss in patients with asthma, and in female subjects specifically. This may result from altered estrogen action, which affects lung development and/or airway remodeling. Further studies on ESR1 gene variations are important to understand better the origin of sex differences in asthma. Variations in the gene encoding estrogen receptor alpha are associated with BHR and a more rapid annual lung function decline, especially in female subjects. Even though this has no diagnostic or clinical implication, it may open avenues for future sex-specific treatment in asthma.

Estrogen-Receptor Polymorphisms and Effects of Estrogen Replacement on High-Density Lipoprotein Cholesterol in Women With Coronary Disease

Although endogenous and exogenous estrogens do increase plasma levels of high-density lipoprotein (HDL) cholesterol, their effects vary considerably. Family studies suggest this may in part result from allelic variants inthe gene encoding estrogen receptor-alpha (ER-a), also known as estrogen receptor 1 (ESR1), which may alter its expression or function. This would be consistent with the functionally important gene variants already identified as encoding steroid receptors, such as receptors for androgens, mineralocorticoids, and glucocorticoids. This study examined the relation between 10 sequence variants in ER-a, including two newly identified ER-a polymorphisms, and HDL cholesterol responses to hormone replacement therapy (HRT). Participants were 309 women with coronary artery disease who were enrolled in the Estrogen Replacement and Atherosclerosis Trial. The women received 0.625 mg of conjugated equine estrogen orally each day, estrogen plus 2.5 mg of medroxyprogesterone acetate, or placebo, and were followed for 3.2 years on average. The IVS1-401 C/C genotype was identified in 18.9% of the study population. After adjusting for age, race, diabetes, body mass index, smoking, alcohol intake, and frequency of exercise, these women had HDL cholesterol levels more than twice those found in the other women (13.1 vs. 6 mg/dl). Only the HDL subfraction 3 (HDL3) was affected. This effect was noted in women given combined estrogen/progestin therapy and those receiving estrogen alone as HRT. Similar patterns of response to HRT were noted for three other highly linked ER-a intron 1 polymorphisms close to the VSI-401 site. Despite the favorable changes in HDL cholesterol, angiographically defined coronary artery disease did not progress less rapidly in women bearing the IVSI-401 C/C genotype. None of the other ER-a polymorphisms studied were associated with an altered response of HDL cholesterol to HRT. These findings support the possibility of using genetic screening to reach decisions on HRT to maximize the well-being of postmenopausal women. The actual effects of different ER-a genotypes on clinical cardiovascular events remain to be determined.

Estrogen modulates norepinephrine-induced accumulation of adenosine cyclic monophosphate in a subpopulation of immortalized luteinizing hormone-releasing hormone secreting neurons from the mouse hypothalamus

A subpopulation of luteinizing hormone-releasing hormone (LHRH)-producing cells that express the intermediate filament protein vimentin and the neuronal marker neurofilament 145, but not neurofilament 200 nor glial fibrillary acidic protein, has been isolated from GT1–7 cultures. These cells express the mRNA encoding estrogen receptor alpha (ERα) and respond to physiological concentrations of 17β-estradiol (E 2) by reducing the accumulation of cyclic adenosine monophosphate induced by norepinephrine, but not that induced by direct activation of adenylate cyclase. These results indicate that the activity of LHRH-producing neurons may be directly modulated by estrogen. In addition, they are suggestive of an estrogen-dependent desensitization of the β-adrenoceptor in these cells.