7 research outputs found
Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society
Fused in sarcoma (FUS) protein lacking nuclear localization signal (NLS) and major RNA binding motifs triggers proteinopathy and severe motor phenotype in transgenic mice.
Dysfunction of two structurally and functionally related proteins, FUS and TAR DNA-binding protein of 43 kDa (TDP-43), implicated in crucial steps of cellular RNA metabolism can cause amyotrophic lateral sclerosis (ALS) and certain other neurodegenerative diseases. The proteins are intrinsically aggregate-prone and form non-amyloid inclusions in the affected nervous tissues, but the role of these proteinaceous aggregates in disease onset and progression is still uncertain. To address this question, we designed a variant of FUS, FUS 1-359, which is predominantly cytoplasmic, highly aggregate-prone, and lacks a region responsible for RNA recognition and binding. Expression of FUS 1-359 in neurons of transgenic mice, at a level lower than that of endogenous FUS, triggers FUSopathy associated with severe damage of motor neurons and their axons, neuroinflammatory reaction, and eventual loss of selective motor neuron populations. These pathological changes cause abrupt development of a severe motor phenotype at the age of 2.5-4.5 months and death of affected animals within several days of onset. The pattern of pathology in transgenic FUS 1-359 mice recapitulates several key features of human ALS with the dynamics of the disease progression compressed in line with shorter mouse lifespan. Our data indicate that neuronal FUS aggregation is sufficient to cause ALS-like phenotype in transgenic mice
Breast cancer adaptive resistance: HER2 and cancer stem cell repopulation in a heterogeneous tumor society.
PurposeThe lethal effects of cancer are associated with the enhanced tumor aggressiveness in recurrent and metastatic lesions that show resistant phenotype to anti-cancer therapy, a major barrier to improving overall survival of cancer patients. The presence of heterogeneous populations of cancer cells within a specific tumor including the tumor-initiating cells or so-called cancer stem cells (CSCs) has linked the acquired resistance (AR, or adaptive resistance). Herein, we discuss the CSC-mediated tumor repopulation in AR of breast cancer in this review.MethodsWe emphasize a dynamic feature of gene induction in tumor cells that undergo long-term treatment, and describe a specific HER2-NF-κB-HER2 pro-survival pathway that can be initiated in breast CSCs upon radiation therapy.ResultsElucidation of HER2-induced pro-survival networks, specifically the force driving tumor repopulation due to radioresistant CSCs during anticancer therapies, will have a significant impact on the generation of new diagnostic and therapeutic targets to control of recurrent and metastatic breast tumors