The gold standard for determining the tumorigenic potential of human cancer cells is a xenotransplantation into immunodeficient mice. Higher tumorigenicity of cells is associated with earlier tumor onset. Here, we used xenotransplantation to assess the tumorigenic potential of human breast cancer cells following RNA interference-mediated inhibition of over 5000 genes. We identify 16 candidate tumor suppressors, one of which is the zinc-finger transcription factor SALL1. Analyzing this particular molecule in more detail, we show that inhibition of SALL1 correlates with reduced levels of CDH1, an important contributor to epithelial-tomesenchymal transition. Furthermore, SALL1 expression led to an increased migration and more than twice as many cells expressing a cancer stem cell signature. Also, SALL1 expression correlates with the survival of breast cancer patients. These findings cast new light on a gene that has previously been described to be relevant during embryogenesis, but not carcinogenesis.
Acute myeloid leukemia (AML) 1 is often disrupted by chromosomal translocations generating oncogenic fusions in human leukemias. However, its role in epithelial cancers has not been extensively investigated. Herein, we show a marked accumulation of AML1 transcripts including a high frequency of a novel alternatively spliced AML1b transcript lacking exon 6 (AML1b Del179À242 ) in ovarian cancer patients. The increases in RNA transcripts for total wild-type AML1 and AML1b Del179À242 are associated with poor patient outcomes. We have shown that although both wild-type AML1b and AML1b Del179À242 are localized to nuclear speckles, AML1b Del179À242 was observed to have dramatically reduced transactivation potential with the plasminogen activator inhibitor-1 promoters and behaved as a weak dominant negative of wild-type AML1b. Wild-type AML1b was found to inhibit the growth of immortalized ovarian epithelial cells (T29) decreasing colony-forming ability. Moreover, we have identified a novel function of AML1b where it inhibits ovarian cell migration. In contrast, AML1b Del179À242 has lost the ability to inhibit both ovarian cell proliferation and migration indicating that the functional effects observed with wild-type AML1b are dependent on amino acids 179-242. Collectively, these studies suggest that deregulated alternative splicing of AML1b transcripts may potentially contribute to the pathophysiology of ovarian cancers.
March 2021Abstracts S183osimertinib. These findings define subgroups of EGFR mutations that may better guide future treatment approaches for atypical EGFR mutations.
pts had bone metastases. Response to chemotherapy was: 4 SD, and 1 PD. Three of 7 corresponding CNV profiles were evaluable for HRD score analysis with 100% positive. Conclusion: Pathogenic BRCA1/2 mutations occur in 1.7% of advanced NSCLC with 71% of somatic mutations suggesting its value for exploring new therapeutic strategies in this population
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