The Musashi RNA-binding proteins in female cancers: insights on molecular mechanisms and therapeutic relevance

Abstract RNA-binding proteins have increasingly been identified as important regulators of gene expression given their ability to bind distinct RNA sequences and regulate their fate. Mounting evidence suggests that RNA-binding proteins are involved in the onset and progression of multiple malignancies, prompting increasing interest in their potential for therapeutic intervention. The Musashi RNA binding proteins Musashi-1 and Musashi-2 were initially identified as developmental factors of the nervous system but have more recently been found to be ubiquitously expressed in physiological tissues and may be involved in pathological cell behavior. Both proteins are increasingly investigated in cancers given dysregulation in multiple tumor entities, including in female malignancies. Recent data suggest that the Musashi proteins serve as cancer stem cell markers as they contribute to cancer cell proliferation and therapy resistance, prompting efforts to identify mechanisms to target them. However, as the picture remains incomplete, continuous efforts to elucidate their role in different signaling pathways remain ongoing. In this review, we focus on the roles of Musashi proteins in tumors of the female – breast, endometrial, ovarian and cervical cancer – as we aim to summarize current knowledge and discuss future perspectives

Immunoglobulin Kappa C Predicts Overall Survival in Node-Negative Breast Cancer

Background: Biomarkers of the immune system are currently not used as prognostic factors in breast cancer. We analyzedthe association of the B cell/plasma cell marker immunoglobulin kappa C (IGKC) and survival of untreated node-negative breast cancer patients.Material and Methods: IGKC expression was evaluated by immunostaining in a cohort of 335 node-negative breast cancer patients with a median follow-up of 152 months. The prognostic significance of IGKC for disease-free survival (DFS) and breast cancer-specific overall survival (OS) was evaluated with Kaplan-Meier survival analysis as well as univariate and multivariate Cox analysis adjusted for age at diagnosis, pT stage, histological grade, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 and human epidermal growth factor receptor 2 (HER-2) status.Results: 160 patients (47.7%) showed strong expression of IGKC. Univariate analysis showed that IGKC was significantlyassociated with DFS (P = 0.017, hazard ratio [HR] = 0.570, 95% confidence interval [CI] = 0.360–0.903) and OS (P = 0.011, HR = 0.438, 95% CI = 0.233–0.822) in the entire cohort. The significance of IGKC was especially strong in ER negative and in luminal B carcinomas. In multivariate analysis IGKC retained its significance independent of established clinical factors for DFS (P = 0.004, HR = 0.504, 95% CI = 0.315–0.804) as well as for OS (P = 0.002, HR = 0.371, 95% CI = 0.196–0.705).Conclusion: Expression of IGKC has an independent protective impact on DFS and OS in node-negative breast cancer

Adjuvant treatment decisions for patients with endometrial cancer in Germany: results of the nationwide AGO pattern of care studies from the years 2013, 2009 and 2006

Purpose In 2013, 2009 and 2006, the Arbeitsgemeinschaft Gynaologische Onkologie evaluated the therapeutic approaches for endometrial carcinoma and the adherence to their guideline in Germany. Here, the adjuvant treatment decisions were presented. Methods A questionnaire was developed and sent to all 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006, respectively). The results of the questionnaires were compared with the recommendations of the guideline and with each other using Fisher's exact test. Results Responses were available in 40.0 % in 2013, 33.3 % in 2009 and 35.8 % in 2006. Participants recommended external beam radiotherapy (EBRT) in 13 out of 16 requested stages and vaginal brachytherapy (VBT) in only 10 out of 16 requested stages as suggested by the guideline. Comparing the results of 2013 with 2009, less participants used EBRT and VBT in 7 out of 16 and in 6 out of 16 requested stages, respectively. Conversely, more participants offered adjuvant chemotherapy (CT) in 2013 (90.4 %) compared to 61.9 % in 2009 (p < 0.001) and 48.8 % in 2006 (p < 0.001), respectively. However, the stage-adjusted recommendations of CT were not in line with the guideline in 11 out of 15 requested stages. In total, 77.3 % of the participants use a multiple drug schedule with a platinum and a taxane compound. Conclusions The results suggest non-adherence to the guideline concerning the stage-adjusted use of VBT and CT in endometrial carcinoma. These findings emphasize great uncertainties and the need of more clarifying trials. Furthermore, a shift from radiotherapy toward CT is observable

Nationwide analysis on surgical procedures for patients with endometrial cancer in Germany: Results of the AGO pattern of care studies from the years 2013, 2009, and 2006

In 2013, 2009, and 2006, the Arbeitsgemeinschaft Gynakologische Onkologie evaluated the therapeutic approaches and the adherence to their guidelines for endometrial carcinoma (EC) in Germany. Here, we present the results concerning the surgical procedures. A questionnaire was developed and sent to 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006). The results were compared with the recommendations of the guideline and with each other. Responses were available in 40.0 % in 2013, 33.3 % in 2009, and 35.8 % in 2006, respectively. Pelvic lymphadenectomy (LAN) was performed in accordance with the guidelines with some exceptions in 2013, 2009, and 2006, whereas paraaortic LAN was performed in accordance with the guideline only in 2009. Histological high-risk subtypes of EC received pelvic and paraaortic LAN in 2013, 2009, and 2006 in accordance with the guidelines with small exceptions. LAN for Patients, who were postoperatively upstaged or upgraded, was not conducted in accordance with the guidelines in 2013, 2009, and 2006. In 2013, 84.6 % of the participants offered the laparoscopic approach (LSA) for hysterectomy and bilateral salpingo-oophorectomy, 63.3 % for pelvic LAN, and 49.1 % for paraaortic LAN, respectively. More participants offered the LSA in 2013 compared to 2009 and 2006 (p values < 0.014). The paraaortic LAN was the second operation on patients, who are postoperatively upstaged, and the LSA was not conducted in accordance with the guideline. Improvements concerning surgical treatment are possible and might lead to higher survival rates and a reduction of morbidity in patients with EC in Germany

Epsin Family Member 3 and Ribosome-Related Genes Are Associated with Late Metastasis in Estrogen Receptor-Positive Breast Cancer and Long-Term Survival in Non-Small Cell Lung Cancer Using a Genome-Wide Identification and Validation Strategy.

In breast cancer, gene signatures that predict the risk of metastasis after surgical tumor resection are mainly indicative of early events. The purpose of this study was to identify genes linked to metastatic recurrence more than three years after surgery.Affymetrix HG U133A and Plus 2.0 array datasets with information on metastasis-free, disease-free or overall survival were accessed via public repositories. Time restricted Cox regression models were used to identify genes associated with metastasis during or after the first three years post-surgery (early- and late-type genes). A sequential validation study design, with two non-adjuvantly treated discovery cohorts (n = 409) and one validation cohort (n = 169) was applied and identified genes were further evaluated in tamoxifen-treated breast cancer patients (n = 923), as well as in patients with non-small cell lung (n = 1779), colon (n = 893) and ovarian (n = 922) cancer.Ten late- and 243 early-type genes were identified in adjuvantly untreated breast cancer. Adjustment to clinicopathological factors and an established proliferation-related signature markedly reduced the number of early-type genes to 16, whereas nine late-type genes still remained significant. These nine genes were associated with metastasis-free survival (MFS) also in a non-time restricted model, but not in the early period alone, stressing that their prognostic impact was primarily based on MFS more than three years after surgery. Four of the ten late-type genes, the ribosome-related factors EIF4B, RPL5, RPL3, and the tumor angiogenesis modifier EPN3 were significantly associated with MFS in the late period also in a meta-analysis of tamoxifen-treated breast cancer cohorts. In contrast, only one late-type gene (EPN3) showed consistent survival associations in more than one cohort in the other cancer types, being associated with worse outcome in two non-small cell lung cancer cohorts. No late-type gene was validated in ovarian and colon cancer.Ribosome-related genes were associated with decreased risk of late metastasis in both adjuvantly untreated and tamoxifen-treated breast cancer patients. In contrast, high expression of epsin (EPN3) was associated with increased risk of late metastasis. This is of clinical relevance considering the well-understood role of epsins in tumor angiogenesis and the ongoing development of epsin antagonizing therapies

Expression of aurora kinase A is associated with metastasis-free survival in node-negative breast cancer patients

Abstract Background Inhibitors targeting the cell cycle-regulated aurora kinase A (AURKA) are currently being developed. Here, we examine the prognostic impact of AURKA in node-negative breast cancer patients without adjuvant systemic therapy (n = 766). Methods AURKA was analyzed using microarray-based gene-expression data from three independent cohorts of node-negative breast cancer patients. In multivariate Cox analyses, the prognostic impact of age, histological grade, tumor size, estrogen receptor (ER), and HER2 were considered. Results Patients with higher AURKA expression had a shorter metastasis-free survival (MFS) in the Mainz (HR 1.93; 95% CI 1.34 – 2.78; P Conclusions AURKA is associated with worse prognosis in estrogen receptor positive breast carcinomas. Patients with the highest AURKA expression (>75% percentile) have a particularly bad prognosis and may profit from therapy with AURKA inhibitors.</p