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Published on: December 11, 2017

Breast cancer resistance protein: molecular target for anticancer drug resistance and

Yoshikazu Sugimoto1, Satomi Tsukahara, Etsuko Ishikawa

  • 1Department of Chemotherapy, Kyoritsu University of Pharmacy, 1-5-30 Shibakoen, Minato-ku, Tokyo 105-8512, Japan. sugimoto-ys@kyoritsu-ph.ac.jp

Cancer Science
|August 20, 2005
PubMed

Insights

Breast cancer resistance protein (BCRP) affects anticancer drug efficacy. Modulators and gene variations can alter BCRP function, impacting drug sensitivity and patient outcomes.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Pharmacology

Background:

  • Breast cancer resistance protein (BCRP) is an ATP-binding cassette transporter that effluxes anticancer drugs, contributing to multidrug resistance.
  • Estrogens and their derivatives can modulate BCRP activity and drug sensitivity.
  • BCRP plays a crucial role in the pharmacokinetics and pharmacodynamics of various anticancer agents.

Purpose of the Study:

  • To investigate the modulators of BCRP-mediated drug resistance, including estrogens and kinase inhibitors.
  • To examine the impact of BCRP gene polymorphisms on transporter function and drug sensitivity.
  • To understand how BCRP function influences cellular accumulation of anticancer agents.

Main Methods:

  • In vitro and in vivo experiments using BCRP-transduced cancer cell lines (A431/BCRP, PC-9/BCRP).
  • Transcellular transport assays to study BCRP substrate specificity.
  • Analysis of BCRP protein and mRNA levels under various treatment conditions.
  • Identification and characterization of functional BCRP gene polymorphisms (C376T and C421A).

Main Results:

  • Estrogens restored drug sensitivity by increasing cellular accumulation of BCRP substrates.
  • The kinase inhibitor gefitinib inhibited BCRP function and reversed drug resistance.
  • Sulfated estrogens and steroidal compounds are transported by BCRP, but not free estrogens.
  • BCRP polymorphisms C376T and C421A result in reduced or absent functional BCRP protein, potentially leading to hypersensitivity to BCRP substrates.
  • Physiological estrogen concentrations reduced BCRP protein expression without affecting mRNA levels.

Conclusions:

  • Modulators like estrogens and gefitinib, as well as BCRP gene polymorphisms, significantly affect BCRP transporter function.
  • These factors can modulate drug sensitivity, pharmacokinetics, and pharmacodynamics in cells and individuals.
  • Understanding BCRP modulation and genetic variations is critical for optimizing cancer therapy and predicting patient response.

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