Inhibition of the transient receptor potential melastatin‐2 ion channel in breast adenocarcinoma cells causes increased DNA damage and decreased proliferation (842.2)

Abstract

The transient receptor potential, melastatin‐2 (TRPM2) cation channel is known for facilitating cell death and is thus targeted for pharmacologic inhibition in debilitating diseases/conditions to decrease tissue injury and prevent cell death. The objective of this study was to determine the role of TRPM2 in breast cancer cells. TRPM2 function in MCF‐7 and MDA‐MB‐231 breast adenocarcinoma cells was investigated using TRPM2 pharmacologic inhibitors or RNAi silencing. In these cells, inhibition or knockdown of TRPM2 led to decreased proliferation and increased cell death after chemotherapeutic treatments. These effects were not observed after equivalent treatments in noncancerous breast cells. Cellular localization studies confirmed the plasma membrane/cytoplasmic localization of the TRPM2 ion channel in noncancerous breast cells. However, it exhibited a unique nuclear localization in breast adenocarcinoma cells. Investigation into a possible nuclear role for TRPM2 demonstrated that inhibition or RNAi silencing of TRPM2 in breast adenocarcinoma cells led to increased DNA damage and decreased genomic integrity as measured by Comet assay. Minimal effects on genomic integrity were observed in noncancerous breast cells after equivalent treatments. This data indicates that TRPM2 facilitates genomic integrity in breast adenocarcinoma cells. Taken together, these results demonstrate that TRPM2 has a novel role in facilitating breast cancer cell genomic integrity, survival, and proliferation. Because these effects are in direct contrast to the pro‐cell death role of TRPM2 in all other tissues and noncancerous cells studied, TRPM2 may represent a novel target in breast cancer treatment. More specifically, TRPM2 pharmacologic inhibition is expected to lead to the selective eradication of breast tumors. These results are therefore expected to provide a basis for inhibiting TRPM2 for the improved treatment of breast cancer patients.