Both oncogenic and tumor-suppressor activities are attributed to the Nuclear Factor kappa B (NF-kB) pathway. Moreover, NF-kB may positively or negatively regulate proliferation. The molecular determinants of these opposing roles of NF-kB are unclear. Using primary human mammary epithelial cells (HMEC) as a model, we show that increased RelA levels and consequent increase in basal transcriptional activity of RelA induces IRF1, a target gene. Induced IRF1 upregulates STAT1 and IRF7, and in consort, these factors induce the expression of interferon response genes. Activation of the interferon pathway down-regulates CDK4 and up-regulates p27 resulting in Rb hypo-phosphorylation and cell cycle arrest. Stimulation of HMEC with IFN-γ elicits similar phenotypic and molecular changes suggesting that basal activity of RelA and IFN-γ converge on IRF1 to regulate proliferation. The anti-proliferative RelA-IRF1-CDK4 signaling axis is retained in ER+/HER2- breast tumors analyzed by The Cancer Genome Atlas (TCGA). Using immuno-histochemical analysis of breast tumors, we confirm the negative correlation between RelA levels and proliferation rate in ER+/HER2- breast tumors. These findings attribute an anti-proliferative tumor-suppressor role to basal RelA activity. Inactivation of Rb, down-regulation of RelA or IRF1, or upregulation of CDK4 or IRF2 rescues the RelA-IRF1-CDK4 induced proliferation arrest in HMEC and are points of disruption in aggressive tumors. Activity of the RelA-IRF1-CDK4 axis may explain favorable response to CDK4/6 inhibition observed in patients with ER+ Rb competent tumors.
Plasmacytoid urothelial carcinoma (PUC) is a very rare variant of urothelial carcinoma with an aggressive clinical course. According to small series reported to date, it is a high grade cancer usually diagnosed at an advanced stage, and with poor prognosis. Descriptions of the cytologic features of this type of carcinoma in literature are limited. Plasmacytoid appearance of tumor cells could cause diagnostic dilemma and potential incorrect diagnosis as multiple myeloma (MM). This report describes cerebrospinal fluid, bone marrow, and urine sediment cytomorphologic and immunocytochemical findings in a patient with meningeal carcinomatosis as the first manifestation of a PUC, initially misdiagnosed as MM with a brief review of the literature.
Breast cancer shows extensive clinical and molecular heterogeneity. Prognostic factors are very important for outcome estimation in individual patients. Nuclear factor κB (NF-κB) and hypoxia-inducible factor 1α (HIF-1α) are transcriptional factors involved in cancerogenesis and in the metastatic spread of tumor cells. The aim of this study was to evaluate the expression of NF-κB and HIF-1α and to correlate the immunohistochemical expression of these markers with the breast cancer subtype and the patient outcome. The retrospective study included 208 cases of ductal invasive breast cancers stratified by the molecular subtype according to the St. Gallen 2011 classification. The Kaplan-Meier survival curve showed that an increased mortality risk was associated with tumors belonging not to the luminal A subtypes but to the Her-2-enriched and luminal B-Her-2-positive subtypes instead (P<0.001). Activation of NF-κB was associated with estrogen-negative tumors (P=0.005). We found a better overall survival in NF-κB-positive tumors in the luminal A subtype (P=0.021). This may be explained as a consequence of a possible tumor-suppressing effect of NF-κB. HIF-1α was related to the overall survival as a poor prognostic factor (P=0.036). In our opinion, the practical relevance of NF-κB and HIF-1α expression as prognostic indicators and potential targets for specific therapies deserve further investigation.
The PCR-mediated Sanger sequencing method was found to be reproducible and reliable. Cytological samples can be used successfully to determine the EGFR mutation status in NSCLC patients providing information for targeted therapy at an early stage of the disease.
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