DREAM, a possible answer to the estrogen paradox of the Women's Health Initiative Trial.

Estrogen is thought to cause proliferation of all estrogen receptor positive (ER+) breast cancers. Paradoxically, in the Women's Health Initiative Trial, estrogen-only hormone replacement therapy reduced the incidence and mortality of low grade, ER+, HER2- breast cancer. We gave estradiol to 19 post-menopausal women with newly diagnosed low-grade, ER+, HER2- breast cancer in a prospective window of opportunity clinical trial and examined the changes in proliferation and gene expression before and after estradiol treatment. Ki67 decreased in 13/19 (68%) patients and 8/13 (62%) showed a decrease in Risk of Recurrence Score. We chose three prototypical estrogen responders (greatest decrease in ROR) and non-responders (no/minimal change in ROR) and applied a differential gene expression analysis to develop pre-treatment (PRESTO-30core) and post-treatment (PRESTO-45surg) gene expression profiles. The PRESTO-30core predicted adjuvant benefit in a published series of tamoxifen, the partial estrogen agonist. Of the 45 genes in the PRESTO-45surg, thirty contain the Cell cycle genes Homology Region (CHR) motif that binds the class B multi-vulva complex (MuvB) a member of the DREAM (Dimerization partner, retinoblastoma-like proteins, E2F, MuvB) complex responsible for reversible cell cycle arrest or quiescence. There was also near uniform suppression (89%) of the remaining DREAM genes consistent with estrogen induced activation of the DREAM complex to mediate cell cycle block after a short course of estrogens. To our knowledge, this is the first report to show estrogen modulation of DREAM genes and suggest involvement of DREAM pathway associated quiescence in endocrine responsive post-menopausal ER+ breast cancers.

MNK1/NODAL Signaling Promotes Invasive Progression of Breast Ductal Carcinoma In Situ.

The mechanisms by which breast cancers progress from relatively indolent ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are not well understood. However, this process is critical to the acquisition of metastatic potential. MAPK-interacting serine/threonine-protein kinase 1 (MNK1) signaling can promote cell invasion. NODAL, a morphogen essential for embryogenic patterning, is often reexpressed in breast cancer. Here we describe a MNK1/NODAL signaling axis that promotes DCIS progression to IDC. We generated MNK1 knockout (KO) or constitutively active MNK1 (caMNK1)-expressing human MCF-10A-derived DCIS cell lines, which were orthotopically injected into the mammary glands of mice. Loss of MNK1 repressed NODAL expression, inhibited DCIS to IDC conversion, and decreased tumor relapse and metastasis. Conversely, caMNK1 induced NODAL expression and promoted IDC. The MNK1/NODAL axis promoted cancer stem cell properties and invasion in vitro. The MNK1/2 inhibitor SEL201 blocked DCIS progression to invasive disease in vivo. In clinical samples, IDC and DCIS with microinvasion expressed higher levels of phospho-MNK1 and NODAL versus low-grade (invasion-free) DCIS. Cumulatively, our data support further development of MNK1 inhibitors as therapeutics for preventing invasive disease. SIGNIFICANCE: These findings provide new mechanistic insight into progression of ductal carcinoma and support clinical application of MNK1 inhibitors to delay progression of indolent ductal carcinoma in situ to invasive ductal carcinoma.

Surgical and oncologic outcomes after robotic radical hysterectomy as compared to open radical hysterectomy in the treatment of early cervical cancer.

OBJECTIVE: The use of robotic radical hysterectomy has greatly increased in the treatment of early stage cervical cancer. We sought to compare surgical and oncologic outcomes of women undergoing robotic radical hysterectomy compared to open radical hysterectomy. METHODS: The clinic-pathologic, treatment, and recurrence data were abstracted through an Institutional Review Board-approved protocol at 2 separate large tertiary care centers in Seattle, Swedish Medical Center and the University of Washington. Data were collected from 2001-2012. Comparisons between the robotic and open cohorts were made for complications, recurrence, progression-free survival (PFS), and overall survival (OS). RESULTS: In the study period, 109 robotic radical hysterectomies were performed. These were compared to 202 open radical hysterectomies. The groups were comparable in terms of age and body mass index (BMI). Length of stay (LOS) was considerably shorter in the robotic group (42.7 vs. 112.6 hours, p<0.001) as was estimated blood loss (EBL; 105.9 vs. 482.6 mL, p<0.001). There were more complications in the open radical hysterectomy group, 23.4% vs. 9.2% in the robotic group (p=0.002). The recurrence rate was comparable between the groups (10.1% vs. 10.4%, p=0.730). In multivariate adjusted analysis, robotic surgery was not a statistically significant predictor of PFS (p=0.230) or OS (0.85). CONCLUSION: Our study, one of the largest multi-institution cohorts of patients undergoing robotic radical hysterectomy, suggest robotic radical hysterectomy leads to comparable oncologic outcomes in the treatment of early stage cervical cancer with improved short-term surgical outcomes such as decreased LOS and EBL.

Diffusion-weighted imaging reflects variable cellularity and stromal density present in breast fibroadenomas.

OBJECTIVE: To determine the underlying histopathologic features influencing apparent diffusion coefficient (ADC) values of breast fibroadenomas. MATERIALS AND METHODS: Biopsy-proven fibroadenomas (n=26) initially identified as suspicious on breast magnetic resonance imaging (MRI) were retrospectively evaluated. Histopathologic assessments of lesion cellularity and stromal type were compared with ADC measures on diffusion-weighted MRI. RESULTS: Presence of epithelial hyperplasia (increased cellularity) and dense collagenous stroma were both significantly associated with lower lesion ADC values (P=.02 and .004, respectively). CONCLUSION: Variations in epithelial cellularity and stromal type influence breast lesion ADC values and may explain the wide range of ADC measures observed in benign fibroadenomas.

Ovarian tumor domain-containing viral proteases evade ubiquitin- and ISG15-dependent innate immune responses.

Ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15) reversibly conjugate to proteins and mediate important innate antiviral responses. The ovarian tumor (OTU) domain represents a superfamily of predicted proteases found in eukaryotic, bacterial, and viral proteins, some of which have Ub-deconjugating activity. We show that the OTU domain-containing proteases from nairoviruses and arteriviruses, two unrelated groups of RNA viruses, hydrolyze Ub and ISG15 from cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domain-containing proteins. Expression of a viral OTU domain-containing protein antagonizes the antiviral effects of ISG15 and enhances susceptibility to Sindbis virus infection in vivo. We also show that viral OTU domain-containing proteases inhibit NF-kappaB-dependent signaling. Thus, the deconjugating activity of viral OTU proteases represents a unique viral strategy to inhibit Ub- and ISG15-dependent antiviral pathways.