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View the Table of Contents for the January 15 issue of Cancer Research.
Page 465
Li et al. Page 501
Transcriptional profiling of human breast cancers has identified five subtypes that correlate with prognosis, therapeutic response, and outcome. The basal subtype is least differentiated, most aggressive, has the shortest time to relapse, and contributes disproportionately to mortality. This subtype lacks ERα, PR, and amplified Her2, underscoring the need for therapeutic targets and definitive markers. Li et al. provide evidence that nestin selectively identifies basal/myoepithelia in the breast and in basal tumors including BRCA1-associated tumors. The authors also demonstrate that nestin expression correlates with δN-p63-a suggesting similarities between basal tumors and mammary regenerative compartments, also providing a definitive marker for basal tumors.
Liao et al. Page 563
Hypoxia occurs in most solid tumors, and increases activity of the HIF transcription factors. Increased expression of the transcription factor HIF-1α is correlated with increased patient mortality in breast cancer. When HIF-1α was conditionally deleted in the mammary epithelium of a transgenic mouse model for metastatic breast cancer, the result was a delayed tumor onset, retarded tumor growth, and decreased pulmonary metastasis. These findings by Liao et al. demonstrate the significance of HIF-1α in breast tumor progression, particularly during the process of metastasis.
The development of radiation sensitizers is driven by a need to provide definitive local-regional control in cases of aggressive disease. Therapeutic hyperthermia is one of the most potent radiation sensitizers identified, but application can be limited by suboptimal thermal doses. Sekhar et al. designed a chemistry-driven drug discovery program for the purpose of developing novel small molecules that enhance the underlying biochemical pathways impacted by heat shock that contribute to radiosensitization. This approach identified (Z)-(±)-2-(1-benzenesulfonylindol-3-ylmethylene)-1-azabicyclo [2.2.2]octan-3-ol and analogs as small molecule enhancers that function at 41°C. These molecules represent a promising tool for the clinical treatment of recurrent tumors by ionizing radiation.
Huang et al. Page 765
Development of drug resistance is a major challenge in cancer chemotherapy using doxorubicin (DOX). By screening the collection of Saccharomyces cerevisiae deletion strains to identify DOX-resistant mutants, Huang et al. discovered that the SUMO pathway is a major determinant of DOX cytotoxicity in yeast. Cumulatively, their results reveal that SUMO modification of proteins mediates the DOX cytotoxicity in yeast, at least partially, by modification of septins and of proteins that control the intracellular drug concentration.