Understanding the mechanism of breast cancer cell radioresistance and the associated selection pressure, tumor recurrence, would help us to develop molecular interventions and achieve disease/progression-free survival in patients with cancer. In the present study, we investigated the molecular mechanisms prompted in breast cancer cells in response to clinical radiation and the associated coordination of intra- and inter-cellular signaling that orchestrate radioresistance and tumor relapse/recurrence. Our findings showed that clinical doses of radiation increase NF-κB transcription and DNA-binding activity. Further, radiation exposure resulted in de novo TNF-α synthesis and secretion. An NF-κB gene manipulation approach revealed that NF-κB triggered NF-κB-mediated TNF-α transcriptional activity. NF-κB DNA binding kinetic analysis demonstrated both sustained and dual phase NF-κB activation with radiation. Radiation prompted NF-κB-dependent synthesis/secretion of TNF-α, a requisite for the second phase of NF-κB activation and maintenance. Radiation-associated NF-κB-dependent secretion of TNF-α from irradiated cells also activated NF-κB in the non-irradiated, non-targeted bystander cells. Together, these findings demonstrated that radiation-triggered NF-κB-dependent TNFα secretion is critical for self-sustenance of NF-κB (through autocrine positive feedback signaling) and for coordinating bystander response (through intercellular signaling: de novo activation of NF-κB in bystander cells) after radiation exposure. Further, the data suggest that this NF-κB→TNF-α→NF-κB feedback-dependent self-sustenance of NF-κB could drive the selection pressure (proliferation, clonal expansion) of surviving breast cancer cells and subsequent tumor relapse/recurrence.

Note: This abstract was not presented at the meeting.

Citation Format: Hui Yu, Natarajan Aravindan, Ji Xu, Mohan Natarajan. Molecular mechanism underlying breast cancer cell radioresistance: role of radiation-induced NF-KB self-sustenance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5856. doi:10.1158/1538-7445.AM2017-5856

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.