Nuclear Basic Fibroblast Growth Factor Regulation of Triple-­Negative Breast Cancer Dormancy/Recurrence

Abstract

<p>Chemotherapy remains the only available treatment for triple-negative (TN) breast cancer. Although some TN breast cancers respond initially to neoadjuvant chemotherapy, the majority of patients die within three years of treatment due to recurrent tumor growth. Developing ex vivo models for TN breast cancer recurrence and defining responsible molecules will be crucial to developing effective combination therapies for TN breast cancer patients. We have developed an in vitro model of TN breast cancer dormancy/recurrence. Short-term exposure of tumor cells to chemotherapy at clinically relevant doses enriches for a dormant tumor cell population. Several days after removing chemotherapy, dormant tumor cells regain proliferative ability and establish colonies, resembling tumor recurrence. Tumor cells from "recurrent" colonies exhibit increased chemotherapy resistance, resembling therapy resistance of recurrent tumors in patients. Furthermore, we identify a novel signaling axis [nuclear bFGF/DNA-dependent protein kinase (DNA-PK)] supported by chemotherapy-enriched dormant TN breast cancer cells. This signaling axis drives accelerated DNA repair in chemo-residual TN breast cancer cells. Targeting this axis with either with a bFGF shRNA or DNA-PK small molecule inhibitor blocks recurrent colony formation. Using the Oncomine gene expression database, we found that bFGF expression in tumor samples from TN breast cancer patients predicts five year tumor recurrence following neoadjuvant chemotherapy treatment. Finally, we demonstrate that recurrent tumor cells exhibit increased invasiveness, reflecting the aggressive behavior of recurrent tumors in patients. Collectively, these studies identify a novel signaling axis in TN breast cancer that likely contributes to tumor recurrence and provide molecular targets for developing future therapeutics against TN breast cancer.</p>