Reversing Anoikis Resistance in Triple-Negative Breast Cancer
Abstract
During the second year of this idea expansion grant, we addressed Aim1, which was to determine if restoration of miR-200c and inhibition of miR-222 can enhance TNBC differentiation in 3D culture. Additionally, restoration of miR-200c decreases the amount of xCT protein, which regulates intracellular glutathione levels). We also completed tasks in Aim 2 to identify the mechanisms by which TNBC cells resist anoikis. We confirmed that TNBC regulators of reactive oxygen species such as xCT and stress and inflammatory pathway genes including COX2 in suspension. Lastly, we determined that components of the kynurenine pathway (KP) increases when TNBC are surviving in suspension culture and restoration of miR-200c to TNBC reduces the rate limiting enzyme in this pathway (TDO2), another enzyme and also reduces the receptor for kynurenine (AhR). Lastly we have now identified splicing factors affected by restoration of miR-200c to TNBC and identify several critical splicing factors and splicing events altered by this miRNA that likely affect epithelial versus mesenchymal pheonotype (differentiation state). Our study continues to generate mechanistic and pre-clinical data necessary to determine if manipulation of these key miRNAs or their downstream targets has potential as a form of differentiation therapy for TNBC, for which there is currently no effective targeted treatment.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2015
- Accession Number
- AD1007497
Entities
People
- Jennifer K Richer
Organizations
- University of Colorado Boulder