Preclinical Study Identifies Potential Therapeutic Target for Resistance to Radiotherapy in Breast Cancer

By: Joshua D. Madera, MD
Posted: Tuesday, June 27, 2023

Investigative efforts to overcome radiotherapy resistance in patients with breast cancer may have led to the development of a novel therapeutic strategy, according to a study published in Breast Cancer Research. This approach targets protein kinase C-zeta (PKC-ζ) to counteract the normal functioning of the extra vesicular transforming growth factor beta-1 (TGF-β1_EV), which may decrease the accumulation of regulatory T cells and reduce resistance to radiotherapy, speculated Professor Fayun Zhang, of the Chinese Academy of Sciences, Beijing, and colleagues.

A variety of PKC isoforms from breast cancer cells were collected and sequentially aligned, speculated, and experimentally confirmed to identify the superoxide-zinc-PKC-ζ–TGF-β1_EV pathway. Cells were subjected to extensive cellular and molecular testing including flow cytometry analysis, quantitative real-time polymerase chain reaction, and Western blotting. In addition, cells were injected into mice vectors to measure tumor growth and overall survival after treatment with radiotherapy at varying Gy doses.

Following the completion of radiotherapy, the observed breast cancer tissues demonstrated elevated expression of intratumoral TGF-β1, primarily located in the extracellular vesicles. Furthermore, evidence of increased infiltration of T-regulatory cells in the breast cancer tissues was revealed. Moreover, elevated secretory levels of TGF-β1_EV and an increased number of T-regulatory cells were identified because of radiotherapy-induced expression and phosphorylation of PKC-ζ.

Radiotherapy efficacy was significantly improved with the use of the flavonoid naringenin compared with the monoclonal antibody 1D11, with a less-pronounced side-effect profile. It is speculated that naringenin functions through the inhibition of the radiation-activated superoxide-zinc-PKC-ζ–TGF-β1_EV pathway.

“In summary, our data substantiate naringenin to be a promising candidate for the development of potential anti–TGF-β1 agents to overcome radiotherapy resistance,” the researchers noted.

Disclosure: The study authors reported no conflicts of interest.

Breast Cancer Research

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