Jose Luis Lopez-Guerra

Loss of the tumor suppressor spinophilin (PPP1R9B) increases the cancer stem cell population in breast tumors

The spinophilin (Spn, PPP1R9B) gene is located at 17q21.33, a region frequently associated with microsatellite instability and loss of heterozygosity, especially in breast tumors. Spn is a regulatory subunit of phosphatase1a (PP1), which targets the catalytic subunit to distinct subcellular locations. Spn downregulation reduces PPP1CA activity against the retinoblastoma protein, pRb, thereby maintaining higher levels of phosphorylated pRb. This effect contributes to an increase in the tumorigenic properties of cells in certain contexts. Here, we explored the mechanism of how Spn downregulation contributes to the malignant phenotype and poor prognosis in breast tumors and found an increase in the stemness phenotype. Analysis of human breast tumors showed that Spn mRNA and protein are reduced or lost in 15% of carcinomas, correlating with a worse prognosis, a more aggressive tumor phenotype and triple-negative tumors, whereas luminal tumors showed high Spn levels. Downregulation of Spn by shRNA increased the stemness properties along with the expression of stem-related genes (Sox2, KLF4, Nanog and OCT4), whereas ectopic overexpression of Spn cDNA reduced these properties. Breast tumor stem cells appeared to have low levels of Spn mRNA, and Spn loss correlated with increased stem-like cell appearance in breast tumors as indicated by an increase in CD44+/CD24- cells. A reduction of the levels of PPP1CA mimicked the cancer stem-like cell phenotype of Spn downregulation, suggesting that the mechanism of Spn involves PP1a. These increased cancer stem cell-like properties with reduced Spn might account for the malignant phenotype observed in Spn-loss tumors and may contribute to a worse patient prognosis.

High casein kinase 1 epsilon levels are correlated with better prognosis in subsets of patients with breast cancer.

Reliable biological markers that predict breast cancer (BC) outcomes after multidisciplinary therapy have not been fully elucidated. We investigated the association between casein kinase 1 epsilon (CK1ε) and the risk of recurrence in patients with BC. Using 168 available tumor samples from patients with BC treated with surgery +/− chemo(radio)therapy, we scored the CK1ε expression as high (≥1.5) or low (<1.5) using an immunohistochemical method. Kaplan-Meier analysis was performed to assess the risk of relapse, and Cox proportional hazards analyses were utilized to evaluate the effect of CK1ε expression on this risk. The median age at diagnosis was 60 years (range 35-96). A total of 58% of the patients underwent breast conservation surgery, while 42% underwent mastectomy. Adjuvant chemotherapy and radiation therapy were administered in 101 (60%) and 137 cases (82%), respectively. Relapse was observed in 24 patients (14%). Multivariate analysis found high expression of CK1ε to be associated with a statistically significant higher disease-free survival (DFS) in BC patients with wild-type p53 (Hazard ratio [HR] = 0.33; 95% CI, 0.12-0.91; P = 0.018) or poor histological differentiation ([HR] = 0.34; 95% CI, 0.12-0.94; P = 0.039) or in those without adjuvant chemotherapy ([HR] = 0.11; 95% CI, 0.01-0.97; P = 0.006). Our data indicate that CK1ε expression is associated with DFS in BC patients with wild-type p53 or poor histological differentiation or in those without adjuvant chemotherapy and thus may serve as a predictor of recurrence in these subsets of patients.

Long-term outcomes after radiosurgery for glomus jugulare tumors

Aims and background: The treatment of glomus jugulare tumors (GJT) remains controversial due to high morbidity. Historically, these tumors have primarily been managed surgically. The purpose of this retrospective review was to assess the tumor and clinical control rates as well as long-term toxicity of GJT treated with radiosurgery. Methods: Between 1993 and 2014, 30 patients with GJT (31 tumors) were managed with radiosurgery. Twenty-one patients were female and the median age was 59 years. Twenty-eight patients (93%) were treated with radiosurgery, typically at 14 Gy (n = 26), and 2 patients (7%) with stereotactic radiosurgery. Sixteen cases (52%) had undergone prior surgery. Results: The mean follow-up was 4.6 years (range 1.5–12). Crude overall survival, tumor control, clinical control, and long-term grade 1 toxicity rates were 97%, 97%, 97%, and 13% (4/30), respectively. No statistically significant risk factor was associated with lower tumor control in our series. Univariate analysis showed a statistically significant association between patients having 1 cranial nerve (CN) involvement before radiosurgery and a higher risk of lack of improvement of symptoms (odds ratio 5.24, 95% confidence interval 1.06–25.97, p = .043). Conclusions: Radiosurgery is an effective and safe treatment modality for GJT. Patients having 1 CN involvement before radiosurgery show a higher risk of lack of improvement of symptoms.