Estrogen receptor ␣ (ER␣)3 is a member of the steroid/nuclear receptor family of transcription regulators and mediates cell growth and metastasis and resistance to apoptosis and immunosurveillance (1-5). ER␣ is activated by binding of 17␤-estradiol (E 2 ), or by the epidermal growth factor-activated extracellular signal-regulated kinase pathway and other signal transduction pathways (6). ER␣-mediated gene transcription contributes to the development and spread of breast, uterine, and liver cancer (5,7,8). A role for ER action in ovarian cancer is supported by the recent finding that endocrine therapy is effective against relapsed ER-containing ovarian cancers (9, 10). Aromatase inhibitors that inhibit estrogen production and tamoxifen (Tam) and other selective estrogen receptor modulators (SERMs) are mainstays in treatment of estrogen-dependent cancers and have played an important role in developing our understanding of ER action (5,7,11,12). Tam and other SERMs work by competing with estrogens for binding in the ligand binding pocket of ER. Over time, tumors usually become resistant to tamoxifen and other SERMs (13-15), requiring new strategies to inhibit ER␣ action.In the best characterized model for ER action, ER␣ activates gene transcription by binding to palindromic estrogen response element (ERE) DNA and ERE half sites (4,16, 17). Thus, an alternative to current approaches that primarily target ER action at the level of ligand binding is to target ER␣ at the level of its interaction with ERE DNA. Although targeting protein binding to DNA is attractive, until recently this approach was questioned, because small molecules may not disrupt the large interaction surfaces of protein⅐DNA and protein⅐protein complexes (18). However, several recent studies support the feasi-

Endometriosis is a chronic gynecological disease that affects approximately 1 in 10 women of reproductive age. Symptoms of severe pelvic pain, infertility, fatigue, and abnormal menstruation can cause significant negative effects on an individual’s physical and mental health, including interactions with their family, friends, and health care providers. Stigma associated with endometriosis has been under-studied and is rarely discussed in current literature. Herein, this paper aims to provide a brief overview of published literature to explore and establish the plausibility of stigma as a driver of suboptimal psychosocial well-being and diagnostic delay among individuals living with endometriosis. We present the clinical characteristics and physical and mental health consequences associated with endometriosis, highlight several theoretical constructs of stigma, and review the limited studies documenting women’s lived experiences of endometriosis-related stigma. To mitigate harmful effects of this phenomenon, we recommend increasing efforts to assess the prevalence of and to characterize endometriosis-related stigma, implementing awareness campaigns, and developing interventions that combat the multidimensional negative effects of stigma on timely care, treatment, and quality of life for individuals living with endometriosis.

The mechanisms responsible for 17␤-estradiol (E 2 )-stimulated breast cancer growth and development of resistance to tamoxifen and other estrogen receptor ␣ (ER␣) antagonists are not fully understood. We describe a new tool for dissecting ER␣ action in breast cancer, p-fluoro-4-(1,2,3,6,-tetrahydro-1,3-dimethyl-2-oxo-6-thionpurin-8-ylthio) (TPSF), a potent small-molecule inhibitor of estrogen receptor ␣ that does not compete with estrogen for binding to ER␣. TPSF noncompetitively inhibits estrogen-dependent ER␣-mediated gene expression with little inhibition of transcriptional activity by NF-B or the androgen or glucocorticoid receptor. TPSF inhibits E 2 -ER␣-mediated induction of the proteinase inhibitor 9 gene, which is activated by ER␣ binding to estrogen response element DNA, and the cyclin D1 gene, which is induced by tethering ER␣ to other DNA-bound proteins. TPSF inhibits anchorage-dependent and anchorage-independent E 2 -ER␣-stimulated growth of MCF-7 cells but does not inhibit growth of ER-negative MDA-MB-231 breast cancer cells. TPSF also inhibits ER␣-dependent growth in three cellular models for tamoxifen resistance; that is, 4-hydroxytamoxifen-stimulated MCF7ER␣HA cells that overexpress ER␣, fully tamoxifen-resistant BT474 cells that have amplified HER-2 and AIB1, and partially tamoxifen-resistant ZR-75 cells. TPSF reduces ER␣ protein levels in MCF-7 cells and several other cell lines without altering ER␣ mRNA levels. The proteasome inhibitor MG132 abolished down-regulation of ER␣ by TPSF. Thus, TPSF affects receptor levels at least in part due to its ability to enhance proteasome-dependent degradation of ER␣. TPSF represents a novel class of ER inhibitor with significant clinical potential. Estrogen receptor ␣ (ER␣)3 is a well studied member of the steroid/nuclear receptor family of transcription regulators. ER␣ acts in the nucleus to regulate gene expression by binding to estrogen response elements (EREs) and related DNA sequences (1-4) and through association with transcription factors bound at SP1 and AP-1 DNA binding sites (4 -7). In response to high affinity estrogen binding, ER␣ dimerizes, binds to ERE DNAs, and undergoes a conformational change in the ligand binding domain that facilitates the recruitment of coactivators (8). Bound coactivators promote assembly of a multiprotein complex that enables chromatin remodeling and stabilization of an active transcription complex (9 -11). In contrast, antagonist-occupied ER␣ recruits corepressors (12).At detection, growth of most human breast cancers depends on 17␤-estradiol (E 2 ) binding to ER␣ (13-16). Treatment strategies that inhibit estrogen-dependent breast cancer include selective ER modulators such as tamoxifen, which binds in the ER␣ ligand binding pocket, and aromatase inhibitors, which block estrogen production. Nearly half of patients treated with aromatase inhibitors develop resistance (17). The long-term effectiveness of tamoxifen is limited by the development of resistance in nearly all patients with metastatic breast cancer and in ϳ4...

Background In the United States, women are at a higher risk of developing vision impairment or a serious eye disease (such as age-related macular degeneration, thyroid eye disease, or chronic dry eye disease) than men. Disparities in eye diseases due to biology widen even further when considering factors such as social determinants of health; gaps in research data, literature, and policy; insufficient provider and patient education; and limitations in screening and treatment options. Sex and gender disparities in eye health are clinically under-addressed and burdensome on both patient quality of life and the health care and economic systems, resulting in a pressing population health issue that negatively impacts women. Design The Society for Women’s Health Research convened a working group of expert clinicians, researchers, and patient advocates to review the current state of science regarding sex and gender disparities in women’s eye health, identify knowledge gaps and unmet needs, and explore better means to advance research, improve patient care, and raise awareness of key issues. Discussion The SWHR Women’s Eye Health Working Group identified priority areas in research, clinical care, and education to reduce disparities and improve patient care in women’s eye health. The working group recommends using a systems approach that incorporates a comprehensive research framework with a sex and gender lens to guide future work and that increases health care provider and public education, as well as engagement by expanding partnerships among ophthalmologic providers, researchers, and non-vision stakeholders.

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