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Breast Cancer Research and Treatment

, Volume 96, Issue 1, pp 1–15 | Cite as

Sodium/potasium ATPase (Na+, K+-ATPase) and ouabain/related cardiac glycosides: a new paradigm for development of anti- breast cancer drugs?

  • Jin-Qiang Chen
  • Ruben G. Contreras
  • Richard Wang
  • Sandra V. Fernandez
  • Liora Shoshani
  • Irma H. Russo
  • Marcelino Cereijido
  • Jose Russo
Review

Summary

Prolonged exposure to 17β-estradiol (E2) is a key etiological factor for human breast cancer. The biological effects and carcinogenic effects of E2 are mediated via estrogen receptors (ERs), ERα and ERβ. Anti-estrogens, e.g. tamoxifen, and aromatase inhibitors have been used to treat ER-positive breast cancer. While anti-estrogen therapy is initially successful, a major problem is that most tumors develop resistance and the disease ultimately progresses, pointing to the need of developing alternative drugs targeting to other critical targets in breast cancer cells. We have identified that Na+, K+-ATPase, a plasma membrane ion pump, has unique/valuable properties that could be used as a potentially important target for breast cancer treatment: (a) it is a key player of cell adhesion and is involved in cancer progression; (b) it serves as a versatile signal transducer and is a target for a number of hormones including estrogens and (d) its aberrant expression and activity are implicated in the development and progression of breast cancer. There are several lines of evidence indicating that ouabain and related digitalis (the potent inhibitors of Na+, K+-ATPase) possess potent anti-breast cancer activity. While it is not clear how the suggested anti-cancer activity of these drugs work, several observations point to ouabain and digitalis as being potential ER antagonists. We critically reviewed many lines of evidence and postulated a novel concept that Na+, K+-ATPase in combination with ERs could be important targets of anti-breast cancer drugs. Modulators, e.g. ouabain and related digitalis could be useful to develop valuable anti-breast cancer drugs as both Na+, K+-ATPase inhibitors and ER antagonists.

Keywords

adhesion junctions breast cancer estrogens estrogen receptors (ERs) estrogen receptor antagonist K+-ATPase Na+ ouabain tight junctions 

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Copyright information

© Springer 2005

Authors and Affiliations

  • Jin-Qiang Chen
    • 1
  • Ruben G. Contreras
    • 2
  • Richard Wang
    • 1
  • Sandra V. Fernandez
    • 1
  • Liora Shoshani
    • 2
  • Irma H. Russo
    • 1
  • Marcelino Cereijido
    • 2
  • Jose Russo
    • 1
  1. 1.Breast Cancer Research LaboratoryFox Chase Cancer CenterPhiladelphiaUSA
  2. 2.Department of Physiology, Biophysics, and NeurosciencesCenter for Research and Advanced StudiesCINVESTAV, Mexico CityUSA

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