Mechanistic and Therapeutic Implications of Spliceosomal Gene Mutations in ER+ Breast Cancer
Abstract
Recent evidence has revealed that altered mRNA splicing is a mechanism by which tumors can derive constitutive, tumor-promoting signals. Recurrent, somatic mutations in the core RNA splicing factor SF3B1 have been found in several malignancies. Through analyses of metastatic breast cancer patients at our center, we have noted hotspot mutations in SF3B1 in up to 6 percent of cases and these are strongly associated with the ER+/HER2- subtype and inferior outcomes in patients. We therefore conducted studies to understand the potential implications of SF3B1 mutations on breast cancer pathogenesis and have so far found that expression of the most common mutant, K700E, leads to characteristic alterations in RNA splicing, promotes the invasiveness and lethality of PIK3CA mutant breast cancer, and increases the sensitivity of PIK3CA mutant breast cancer cells to AKT inhibition. Based on these observations, we are further studying the consequences of SF3B1 mutation on breast cancer progression and sensitivity to spliceosomal targeted therapy.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2020
- Accession Number
- AD1114535
Entities
People
- Omar Abdel-Wahab
- Sarat Chandarlapaty
Organizations
- Memorial Sloan Kettering Cancer Center