Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer RESEARCH

Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy–resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independent mutant ESR1 genomic binding that is significantly altered from wild-type ESR1. The D538G mutation impacted expression, including a large set of nonestrogen-regulated genes, and chromatin accessibility, with most affected loci bound by mutant ESR1. Mutant ESR1 is distinct from constitutive ESR1 activity because mutant-specific changes are not recapitulated with prolonged estrogen exposure. Overall, the D538G mutant ESR1 confers estrogen-independent activity while causing additional regulatory changes in endometrial cancer cells that are distinct from breast cancer cells.
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: RESEARCH Source Type: research

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Estrogen receptor 1 (ESR1) mutations have been identified in hormone therapy–resistant breast cancer and primary endometrial cancer. Analyses in breast cancer suggest that mutant ESR1 exhibits estrogen-independent activity. In endometrial cancer, ESR1 mutations are associated with worse outcomes and less obesity, however, experimental investigation of these mutations has not been performed. Using a unique CRISPR/Cas9 strategy, we introduced the D538G mutation, a common endometrial cancer mutation that alters the ligand binding domain of ESR1, while epitope tagging the endogenous locus. We discovered estrogen-independ...
Source: Genome Research - Category: Genetics & Stem Cells Authors: Tags: RESEARCH Source Type: research
In this study, we aimed to estimate the frequency of premalignant and malignant lesions in endometrial polyps, and to evaluate associated clinical and demographic factors. A literature search was performed in major databases and the gray literature using the terms polyps OR endometrial polyp AND endometrial neoplasms OR endometrial cancer OR endometrial hyperplasia OR malignan*. Studies describing the frequency of premalignant and malignant lesions in endometrial polyps and any clinical or demographic factors associated with malignant lesions extracted using hysteroscopy were considered eligible. Independent investigators ...
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
The objective of our study was to estimate the frequency of pre-malignant and malignant lesions in endometrial polyps and to evaluate associated clinical and demographic factors. A literature search was performed in major databases and the gray literature using the terms polyps OR endometrial polyp AND endometrial neoplasms OR endometrial cancer OR endometrial hyperplasia OR malignan*. Studies describing the frequency of pre-malignant and malignant lesions in endometrial polyps and any clinical or demographic factors associated with malignant lesions extracted using hysteroscopy were considered eligible. Independent invest...
Source: Journal of Minimally Invasive Gynecology - Category: OBGYN Source Type: research
FINDINGSWhen it comes to assessing the risk of estrogen therapy for menopause, how the therapy is delivered — taking a pill versus wearing a patch on one’s skin — doesn’t affect risk or benefit, researchers at UCLA and elsewhere have found. But with the commonly used conjugated equine estrogen, plus progestogen, the dosage does. Higher doses, especially over time, are associated with greater risk of problems, including heart disease and some types of cancer, especially among obese women.BACKGROUNDThe Women ’s Health Initiative established the potential of estrogen therapy to increase or decrea...
Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
Conclusion This study provides more evidence of the link between excess body fat and 10 cancers. Though the percentage increases sound large, it's important to put these results into context. For example, the baseline risk of postmenopausal cancer was 2.2% – it occurred in 555 of the 24,751 women in the study. For women who hadn't used hormone therapy, this would increase to a risk of 2.7% if they had a BMI of 30 compared with 26, or a waist circumference of 95cm compared with 84cm. This accounts for only an extra 5 cases in every 1,000 women. This large study involved older adults from European countries, so ...
Source: NHS News Feed - Category: Consumer Health News Tags: Cancer Obesity Source Type: news
Conclusions: Weight gain and weight cycling were positively associated with risk of breast and endometrial cancer, respectively. Impact: These data suggest weight cycling and weight gain increase risk of prevalent cancers in postmenopausal women. Adopting ideal body-weight maintenance practices before and after weight loss should be encouraged to reduce risk of incident breast and endometrial cancers. Cancer Epidemiol Biomarkers Prev; 26(5); 779–86. ©2017 AACR.
Source: Cancer Epidemiology Biomarkers and Prevention - Category: Cancer & Oncology Authors: Tags: Research Articles Source Type: research
CONCLUSIONS: Women with intolerable menopausal symptoms may wish to weigh the benefits of symptom relief against the small absolute risk of harm arising from short-term use of low-dose HT, provided they do not have specific contraindications. HT may be unsuitable for some women, including those at increased risk of cardiovascular disease, increased risk of thromboembolic disease (such as those with obesity or a history of venous thrombosis) or increased risk of some types of cancer (such as breast cancer, in women with a uterus). The risk of endometrial cancer among women with a uterus taking oestrogen-only HT is well docu...
Source: Cochrane Database of Systematic Reviews - Category: Journals (General) Authors: Tags: Cochrane Database Syst Rev Source Type: research
Purpose of review: Provide evidence-based recent data on oral micronized progesterone (OMP) and progestins in menopausal hormonal therapy (MHT). Recent findings: Medroxyprogesterone acetate (MPA) increases breast cancer acting through the glucocorticoid receptor; progestins in MHT increase thrombosis more than oral estrogens; MPA, but not OMP or other progestins, increase monocyte cell endothelium adhesion; MPA and estradiol (E2)/MPA have negative brain effects, whereas E2/progesterone (P4) has neuroregenerative brain effects. The ‘window of opportunity’ cardiovascular disease hypothesis is not supported by a r...
Source: Current Opinion in Endocrinology, Diabetes and Obesity - Category: Endocrinology Tags: Reproductive Endocrinology Source Type: research
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