Accession Number:

AD1116584

Title:

Enhancement of Breast Tumor Cell Immunogenicity as a Strategy for Chemosensitization

Descriptive Note:

[Technical Report, Annual Report]

Corporate Author:

Virginia Commonwealth University

Personal Author(s):

Report Date:

2020-08-01

Pagination or Media Count:

46

Abstract:

Epigenetic regulation of tumor cell sensitivity to chemotherapy. The overall thrust of this project has been to establish that genetic and pharmacologic inhibition of NURF will be effective in sensitizing breast tumor cells to chemotherapy, through both direct cell autonomous and indirect cell non-autonomous, immune mediated pathways. To this end, we have shown that suppression of the bromodomain PHD finger transcription factor subunit BPTF of the nucleosome remodeling factor NURF enhances sensitivity of the 4T1 murine breast tumor cell line to yhe topoisomerase II poisons, doxorubicin and etoposide as well as the microtubule, poison, paclitaxel. These effects demonstrated selectivity against the tumor cells for doxorubicin and etoposide, but not paclitaxel, as similar sensitization was not observed for the topoisomerase II poisons in embryonic stem cells. Sensitization to doxorubicin and etoposide with BPTF knockdown was associated with increased DNA damage, to isomerase II crosslinking and autophagy. However, there was no concomitant increase in apoptosis or senescence. Sensitization to doxorubicin was confirmed in animals bearing the syngeneic 4T1 breast tumor cells using both genetic and pharmacologic inhibition of BPTF. The sensitization appeared to be autophagy-dependent. Finally, treatment of 4T1 and MDA-MB231 breast cancer cells with the selective BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF inhibition, including in vivo sensitization to doxorubicin, increased topoisomerase II DNA crosslinks and increased DNA damage. These studies suggest that BPTF could potentially be targeted with small molecule inhibitors to enhance the effectiveness of topo-II targeted cancer chemotherapeutic drugs.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

[A, Approved For Public Release]