Inactivation of cell death is a major step in tumor development, and p53, a tumor suppressor frequently mutated in cancer, is a critical mediator of cell death. While a role for p53 in apoptosis is well established, direct links to other pathways controlling cell death are unknown. Here we describe DRAM (damage-regulated autophagy modulator), a p53 target gene encoding a lysosomal protein that induces macroautophagy, as an effector of p53-mediated death. We show that p53 induces autophagy in a DRAM-dependent manner and, while overexpression of DRAM alone causes minimal cell death, DRAM is essential for p53-mediated apoptosis. Moreover, analysis of DRAM in primary tumors revealed frequent decreased expression often accompanied by retention of wild-type p53. Collectively therefore, these studies not only report a stress-induced regulator of autophagy but also highlight the relationship of DRAM and autophagy to p53 function and damage-induced programmed cell death.
The psychometric properties of the Italian version of the Hospital Anxiety and Depression Scale and its utility as a screening instrument for anxiety and depression in a non-psychiatric setting were evaluated. The questionnaire was administered twice to 197 breast cancer patients randomised in a phase III adjuvant clinical trial: before the start of chemotherapy and at the first follow-up visit. The presence of psychiatric disorders was evaluated at the follow-up visit using the Structured Clinical Interview for DSM-III-R in 132 patients. Factor analyses identified two strictly correlated factors. Crohnbach's alpha for the anxiety and depression scales ranged between 0.80 and 0.85. At follow-up, 50 patients (38%) were assigned a current DSM-III-R diagnosis, in most cases adjustment disorders (24%) or major depressive disorder (10%). Receiver operating characteristics (ROC) analysis was used to test the discriminant validity for both anxiety and depressive disorders. The comparison of the areas under the curve (AUC) between the two scales did not show any difference in identifying either anxiety (P = 0.855) or depressive disorders (P = 0.357). The 14-item total scale showed a high internal consistency (alpha = 0.89 and 0.88) and a high discriminating power for all the psychiatric disorders (AUC = 0.89; 95% CI = 0.83-0.94). The cut-off point that maximised sensitivity (84%) and specificity (79%) was 10. These results suggest that the total score is a valid measure of emotional distress, so that the Italian version of HADS can be used as a screening questionnaire for psychiatric disorders. The use of the two subscales as a 'case identifier' or as an outcome measure should be considered with caution.
Therapies that target estrogen signaling have transformed the treatment of breast cancer. However, the effectiveness of these agents is limited by the development of resistance. Here, an RNAi screen was used to identify modifiers of tamoxifen sensitivity. We demonstrate that CDK10 is an important determinant of resistance to endocrine therapies and show that CDK10 silencing increases ETS2-driven transcription of c-RAF, resulting in MAPK pathway activation and loss of tumor cell reliance upon estrogen signaling. Patients with ER alpha-positive tumors that express low levels of CDK10 relapse early on tamoxifen, demonstrating the clinical significance of these observations. The association of low levels of CDK10 with methylation of the CDK10 promoter suggests a mechanism by which CDK10 expression is reduced in tumors.
This study failed to show the non-inferiority of a shorter trastuzumab administration. 1-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse.
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