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With advances in cancer therapy, reproductive-aged women can look forward to a life post-malignancy. Fortunately, fertility preservation (FP) may provide relief from potential infertility caused by cancer or associated caustic treatments. Outcomes of FP in pre-treatment reproductive-aged women with gliomas have not been previously characterized. Between 2007 and 2018, 10 patients undergoing FP prior to chemotherapy and/or radiation treatment for gliomas were identified at Brigham and Women’s Hospital. They were matched 3:1 to male-factor infertility patients by age ± 1 year. Patients with gliomas had significantly lower baseline anti-Mullerian hormone levels than male-factor infertility controls (2.37 vs 5.16 ng/mL, p = 0.002, log transformed). Despite higher starting (350 vs. 240 IU, p = 0.004) and total gonadotropin doses (4270 vs. 2270 IU, p

PURPOSE: Women with polycystic ovary syndrome (PCOS) have an increased ovarian responsiveness to exogenous recombinant follicle stimulating hormone (rFSH) but also have high rates of obesity, which is known to affect serum FSH concentrations following exogenous injection. The purpose of this study was to compare rFSH absorption and ovarian response between lean and overweight/obese PCOS subjects and normo-ovulatory controls. METHODS: Fourteen women with PCOS aged 18–42 years old with a BMI of 18.5–24.9 kg/m(2) (normal) or 25.0–40.0 kg/m(2) (overweight/obese) and eleven normo-ovulatory controls matched by age and BMI were included. After downregulation with oral contraceptives, participants were administered a single subcutaneous injection of 225 IU rFSH and underwent serial blood draws over 72 h. RESULTS: Lean PCOS subjects exhibited a significantly higher area under the curve (AUC) of baseline-corrected serum FSH over 72 h when compared with overweight/obese PCOS subjects (183.3 vs 139.8 IU*h/L, p = 0.0002), and lean, normo-ovulatory women had a significantly higher AUC FSH when compared with overweight/obese, normo-ovulatory women (193.3 vs 93.8 IU*h/L, p

Background Cancer treatments have significant negative impacts on female fertility, but the impact of cancer itself on fertility remains to be clarified. While some studies have shown that compared with healthy women, those with cancer require higher doses of gonadotropins resulting in decreased oocyte yields, others have shown comparable oocyte yields between the two groups. The purpose of this study is to evaluate whether there is an association between any cancer and/or type of cancer, and response to ovarian stimulation for egg and embryo banking. Methods In this retrospective cohort study, ovarian stimulation cycles performed from June 2007 through October 2014 at a single academic medical center were reviewed to identify those undertaken for women with cancer undergoing fertility preservation (n = 147) or women with no cancer undergoing their first cycle due to male factor infertility (n = 664). Of the 147 women undergoing fertility preservation, 105 had local cancer (Stage I-III solid malignancies) and 42 had systemic cancer (hematologic or Stage IV solid malignancies). Response to ovarian stimulation was compared among these two groups and women with no cancer. Results Adjusting for age and BMI, women with systemic cancer had lower baseline antral follicle counts (AFC) than women with no cancer or local cancer. Women with systemic cancer required higher doses of FSH than women with no cancer or local cancer, and they had higher oocyte to AFC ratios than women with no cancer or local cancer, but greater odds of cycle cancellation as compared to women with no cancer or local cancer. No significant differences were observed among the three groups for duration of stimulation, number of oocytes and mature oocytes retrieved, or number of embryos created. Conclusions Women with cancer achieve similar oocyte and embryo yields as women with no cancer, although those with systemic cancer require higher FSH doses and are at greater risk of cycle cancellation.

More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative–acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment. Cancer Res; 70(23); 9875–85. ©2010 AACR.

Hyperandrogenism is an uncommon diagnosis in postmenopausal women. In this case, we report on a 69-year-old postmenopausal woman who presented with several months of worsening hirsutism of the face, neck, and chin, which was confirmed on examination. Laboratory testing revealed markedly elevated testosterone levels and typical post-menopausal gonadotropin levels. Transvaginal ultrasonography and pelvic and abdominal magnetic resonance imaging (MRI) failed to reveal an ovarian or adrenal abnormality. The patient was a poor surgical candidate and was counseled to start on gonadotropin releasing hormone (GnRH) agonist therapy. Administration of leuprolide resulted in a dramatic decline in testosterone levels. The patient reported significant “hot flashes”, difficulty sleeping, anxiety, and depression secondary to treatment, and patient discontinued leuprolide therapy 3 months after initiation. To our knowledge, this is the first case that describes a woman being treated with a GnRH agonist for hyperandrogenism subsequently discontinuing GnRH agonist treatment due to significant side-effects. This case also highlights the difficulty of prescribing appropriate but off-label use of expensive medications not covered by insurance in a senior population of limited income.

Lung cancer is the leading cause of cancer mortality for women and men in the United States. Given this, there is a need to find new targets to combat lung cancer. This study explores the E1-like ubiquitin-activating enzyme (UBE1L) that associates with the interferon-stimulated gene 15 (ISG15), which complexes with cyclin D1 and other specific proteins. The ubiquitin protease UBP43 removes ISG15 from conjugated proteins. The UBE1L-ISG15-UBP43 pathway was previously proposed to inhibit lung carcinogenesis by repressing cyclin D1 expression. Our prior work is extended here by reporting that UBP43 is enzymatically active in cells. Also, gain of UBP43 expression specifically stabilizes cyclin D1 while UBP43 knock-down destabilizes cyclin D1, but not cyclin E or other D-type cyclins. This occurs by regulating ISG15 complexes with cyclin D1. UBP43 effects on cyclin D1 were not antagonized by cycloheximide treatment. Whether the deconjugase UBP43 was a lung cancer target was independently addressed through engineered gain and loss of UBP43 expression in lung cancer cells. UBP43 knock-down triggered apoptosis in these cells. In contrast, UBP43 over-expression promoted lung cancer cell growth by inhibiting apoptosis. That cyclin D1 plays a key role in conferring these effects was shown by engineered loss of UBP43 along with forced cyclin D1 expression. Cyclin D1 antagonized effects of loss of UBP43. Engineered UBP43 knock-down in lung cancer cells significantly increased apoptosis (P < 0.05), reduced growth (P < 0.05) and inhibited lung cancer formation (P < 0.05) in FVB mice injected via tail veins with syngeneic lung cancer cells. In marked contrast, forced UBP43 over-expression in lung cancer cells antagonized the effects of interferon, cisplatin and all-trans-retinoic acid, indicating that UBP43 can regulate response to anti-neoplastic agents. To ascertain the clinical impact of this pathway, a paired normal-malignant human lung tissue array from 74 cases was examined for immunohistochemical expression profiles of UBP43 and cyclin D1 proteins. Notably, UBP43 was significantly increased in the malignant as compared to the adjacent normal lung tissues (P = 0.04 for adenocarcinoma and P = 0.02 for squamous cell carcinoma). Intriguingly, a direct relationship was found between UBP43 and cyclin D1, validating clinical relevance. Thus, UBP43 knock-down appears to exert its anti-neoplastic effects by destabilizing cyclin D1. Taken together, these findings establish that the deconjugase UBP43 is a tractable target for lung cancer therapy and prevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1655. doi:10.1158/1538-7445.AM2011-1655

All-trans-retinoic acid (RA) successfully treats acute promyelocytic leukemia (APL) at least partly through triggering degradation of the PML/RARα translocation product. Prior work revealed that the E1-like ubiquitin-activating enzyme (UBE1L) associates with the interferon-stimulated gene 15 (ISG15) to repress PML/RARα protein expression. The ubiquitin protease 43 (UBP43) removes ISG15 from conjugated proteins. We derived two different anti-human UBP43 antisera to examine UBP43 protein expression. This study explored whether RA regulates UBP43 expression and if UBP43 affects PML/RARα protein stability as well as growth or apoptosis of APL cells. Retinoid regulation of the UBE1L-ISG15-UBP43 pathway was studied in cultured NB4 APL cells, transgenic APL mice and leukemic cells harvested from APL patients. Whether the deconjugase UBP43 was a therapeutic target was determined through gain and loss of UBP43 expression experiments. This study extends prior work by reporting that RA-treatment induced UBP43 expression in RA-sensitive, but not in RA-resistant NB4 APL cells. This followed an induction of UBE1L and ISG15 expression in RA-sensitive APL cells. UBP43 functions as a negative feedback loop by reversing ISG15 conjugation of PML/RARα protein. Deregulating this loop by UBP43 knock-down repressed APL cell growth by further destabilizing the PML domain of PML/RARα protein. Notably, this triggered apoptosis in APL cells. In contrast, UBP43 over-expression stabilized PML/RARα protein and promoted APL cell growth by inhibiting apoptosis. RA-treatment of a murine transgenic APL model and of de novo cultures of APL cells from patients increased UBE1L, ISG15 and UBP43 expression. Thus, this study found that the deconjugase UBP43 was retinoid regulated in NB4 APL cells as well as in leukemic cells isolated directly from APL patients and in a mouse model for APL. Oncogenic effects of PML/RARα were reversed by UBP43 knock-down, which destabilized PML/RARα protein and triggered apoptosis in APL cells. Taken together, these findings establish UBP43 as a novel molecular pharmacologic target for APL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1594.