Autophagy-dependent sensitization of triple-negative breast cancer models to Topoisomerase II poisons by inhibition of the Nucleosome remodeling factor

Epigenetic regulators can modulate the effects of cancer theraautophagy dependent, based on genetic autophagy inhibition. peutics. To further these observations, we discovered that the Finally, treatment of 4T1, 66cl4, 4T07, MDA-MB-231, but not bromodomain PHD finger transcription factor subunit (BPTF) of ER-positive 67NR and MCF7 breast cancer cells with the selective the nucleosome remodeling factor (NURF) promotes resistance to BPTF bromodomain inhibitor, AU1, recapitulates genetic BPTF doxorubicin, etoposide, and paclitaxel in the 4T1 breast tumor cell inhibition, including in vitro sensitization to doxorubicin, increased line. BPTF functions in promoting resistance to doxorubicin and TOP2-DNA crosslinks and DNA damage. Taken together, these etoposide, but not paclitaxel, and may be selective to cancer cells, as studies demonstrate that BPTF provides resistance to the antitumor a similar effect was not observed in embryonic stem cells. Sensiactivity of TOP2 poisons, preventing the resolution of TOP2 cross-tization to doxorubicin and etoposide with BPTF knockdown (KD) linking and associated autophagy. These studies suggest that BPTF was associated with increased DNA damage, topoisomerase II can be targeted with small-molecule inhibitors to enhance the (TOP2) crosslinking and autophagy; however, there was only a effectiveness of TOP2-targeted cancer chemotherapeutic drugs. modest increase in apoptosis and no increase in senescence. Sensitization to doxorubicin was confirmed in vivo with the syngeneic Implications: These studies suggest NURF can be inhibited phar-4T1 breast tumor model using both genetic and pharmacologic macologically as a viable strategy to improve chemotherapy inhibition of BPTF. The effects of BPTF inhibition in vivo are effectiveness.