A synopsis of global frontiers in fertility preservation.

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of "Oncofertility Around the Globe" to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.

Ovarian cancer in endometriosis: clinical and molecular aspects.

Endometriosis is a gynecological condition characterized by specific histological, molecular and clinical findings, that affects 5-10% of premenopausal women and has been implicated as a precursor for certain types of ovarian cancer. Clinical studies of endometriosis associated ovarian cancer (EAOC) suggest that patients present at a young age with a lower stage and grade of tumor, and are more likely to be premenopausal than women with other ovarian cancers. However, when overall survival is compared between these types of ovarian cancers, there is no difference noted. In addition, EAOC tumors are more likely to be found with a concurrent diagnosis of cancer, most commonly endometrial. Advances in technology, primarily the ability for whole genome sequencing, have led to the discovery of new mutations and further understanding of previously identified genes and pathways associated with EAOCs including PTEN, CTNNB1 (beta-catenin), KRAS, microsatellite instability and ARID1A. This paper will review the most recent clinical and molecular advances in the association of endometriosis and ovarian cancer.

ERß- and prostaglandin E2-regulated pathways integrate cell proliferation via Ras-like and estrogen-regulated growth inhibitor in endometriosis.

In endometriosis, stromal and epithelial cells from the endometrium form extrauterine lesions and persist in response to estrogen (E2) and prostaglandin E2 (PGE2). Stromal cells produce excessive quantities of estrogen and PGE2 in a feed-forward manner. However, it is unknown how estrogen stimulates cell proliferation and survival for the establishment and persistence of disease. Previous studies suggest that estrogen receptor-ß (ERß) is strikingly overexpressed in endometriotic stromal cells. Thus, we integrated genome-wide ERß binding data from previously published studies in breast cells and gene expression profiles in human endometriosis and endometrial tissues (total sample number = 81) and identified Ras-like, estrogen-regulated, growth inhibitor (RERG) as an ERß target. Estradiol potently induced RERG mRNA and protein levels in primary endometriotic stromal cells. Chromatin immunoprecipitation demonstrated E2-induced enrichment of ERß at the RERG promoter region. PGE2 via protein kinase A phosphorylated RERG and enhanced the nuclear translocation of RERG. RERG induced the proliferation of primary endometriotic cells. Overall, we demonstrated that E2/ERß and PGE2 integrate at RERG, leading to increased endometriotic cell proliferation and represents a novel candidate for therapeutic intervention.

Ligand-activated peroxisome proliferator-activated receptor ß/δ modulates human endometrial cancer cell survival.

Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor ß/δ (PPARß/δ) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARß/δ agonists, GW0742 and GW501516, PPARß/δ inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARß/δ-induced effects on cell proliferation and apoptosis was demonstrated using PPARß/δ-selective antagonists and PPARß/δ small interfering RNA in combination with PPARß/δ-selective agonists. Furthermore, we showed that PPARß/δ activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3ß (GSK3ß) dephosphorylation, and increased ß-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPARß/δ activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3ß/ß-catenin pathway. These findings warrant further investigation of PPARß/δ as a therapeutic target in endometrial cancer.

Synthesis and activity of bivalent FKBP12 ligands for the regulated dimerization of proteins.

The total synthesis and in vitro activities of a series of chemical inducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusion proteins has been demonstrated to have broad utility in biological research as well as potential medical applications in gene and cell therapies. The facility and flexibility of preparation make this new class of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein-protein interactions or protein localization. While some congeners possess potency comparable to or better than the first generation natural product-derived CID, FK1012, structure-activity relationships are complex and underscore the need for application-specific compound optimizations.