Thioredoxin-mediated redox regulation of resistance to endocrine therapy in breast cancer

Biochim Biophys Acta. 2013 Aug;1836(1):60-79. doi: 10.1016/j.bbcan.2013.02.005. Epub 2013 Mar 4.

Abstract

Resistance to endocrine therapy in breast carcinogenesis due to the redox regulation of the signal transduction system by reactive oxygen species (ROS) is the subject of this review article. Both antiestrogens and aromatase inhibitors are thought to prevent cancer through modulating the estrogen receptor function, but other mechanisms cannot be ruled out as these compounds also block metabolism and redox cycling of estrogen and are free radical scavengers. Endocrine therapeutic agents, such as, tamoxifen and other antiestrogens, and the aromatase inhibitor, exemestane, are capable of producing ROS. Aggressive breast cancer cells have high oxidative stress and chronic treatment with exemestane, fulvestrant or tamoxifen may add additional ROS stress. Breast cancer cells receiving long-term antiestrogen treatment appear to adapt to this increased persistent level of ROS. This, in turn, may lead to the disruption of reversible redox signaling that involves redox-sensitive phosphatases, protein kinases, such as, ERK and AKT, and transcription factors, such as, AP-1, NRF-1 and NF-κB. Thioredoxin modulates the expression of estrogen responsive genes through modulating the production of H2O2 in breast cancer cells. Overexpressing thioredoxine reductase 2 and reducing oxidized thioredoxin restores tamoxifen sensitivity to previously resistant breast cancer cells. In summary, it appears that resistance to endocrine therapy may be mediated, in part, by ROS-mediated dysregulation of both estrogen-dependent and estrogen-independent redox-sensitive signaling pathways. Further studies are needed to define the mechanism of action of thioredoxin modifiers, and their effect on the redox regulation that contributes to restoring the antiestrogen-mediated signal transduction system and growth inhibitory action.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Oxidation-Reduction
  • Thioredoxins / metabolism*

Substances

  • Antineoplastic Agents, Hormonal
  • Thioredoxins