Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy

James Griffith, Daniel Andrade, Meghna Mehta, William Berry, Doris M. Benbrook, Natarajan Aravindan, Terence S. Herman, Rajagopal Ramesh, Anupama Munshi

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Overexpression of BMI1 in human cancer cells, a member of the polycomb group of repressive complexes, correlates with advanced stage of disease, aggressive clinicopathological behavior, poor prognosis, and resistance to radiation and chemotherapy. Studies have shown that experimental reduction of BMI1 protein level in tumor cells results in inhibition of cell proliferation, induction of apoptosis and/or senescence, and increased susceptibility to cytotoxic agents and radiation therapy. Although a role for BMI1 in cancer progression and its importance as a molecular target for cancer therapy has been established, information on the impact of silencing BMI1 in triple-negative breast cancer (TNBC) and its consequence on radiotherapy have not been well studied. Therefore, in the present study we investigated the potential therapeutic benefit of radiation therapy in BMI1-silenced breast cancer cells and studied the mechanism(s) of radiosensitization. Human MDA-MB-231 and SUM159PT breast cancer cells that were either stably transfected with a lentiviral vector expressing BMI1 shRNA (shBMI1) or control shRNA (shControl) or transient transfection with a BMI1-specific siRNA were used. Silencing of BMI1 resulted in marked reduction in BMI1 both at the mRNA and protein level that was accompanied by a significant reduction in cell migration compared to control cells. Further, BMI1 knockdown produced a marked enhancement of DNA damage as evidenced by Comet Assay and γH2AX foci, resulting in a dose-dependent radiosensitization effect. Molecular studies revealed modulation of protein expression that is associated with the DNA damage response (DDR) and autophagy pathways. Our results demonstrate that BMI1 is an important therapeutic target in breast cancer and suppression of BMI1 produces radiation sensitivity. Further, combining BMI1-targeted therapeutics with radiation might benefit patients diagnosed with TNBC.

Original languageEnglish (US)
Pages (from-to)2382-2390
Number of pages9
JournalOncology reports
Volume37
Issue number4
DOIs
StatePublished - Apr 2017
Externally publishedYes

Keywords

  • Autophagy
  • BMI1
  • Breast cancer
  • DNA damage
  • Radiation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Silencing BMI1 radiosensitizes human breast cancer cells by inducing DNA damage and autophagy'. Together they form a unique fingerprint.

Cite this