Functional SNPs of the breast cancer resistance protein - Therapeutic effects and inhibitor development

Kae Yanase, Satomi Tsukahara, Junko Mitsuhashi, Yoshikazu Sugimoto

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that pumps out various anticancer agents such as 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. We have previously identified three polymorphisms within the BCRP gene, G34A (substituting Met for Val-12), C376T (substituting a stop codon for Gln-126) and C421A (substituting Lys for Gln-141). C421A BCRP-transfected murine fibroblast PA317 cells showed markedly decreased protein expression and low-level drug resistance when compared with wild-type BCRP-transfected cells. In contrast, G34A BCRP-transfected PA317 cells showed a similar protein expression and drug resistance profile to wild-type. The C376T polymorphism would be expected to have a considerable impact as active BCRP protein will not be expressed from a T376 allele. Hence, people with C376T and/or C421A polymorphisms may express low levels of BCRP, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. Estrogens, estrone and 17β-estradiol, were previously found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of anticancer agents. BCRP transports sulfated estrogens but not free estrogens and in a series of screening experiments for synthesized and natural estrogenic compounds, several tamoxifen derivatives and phytoestrogens/flavonoids were identified that effectively circumvent BCRP-mediated drug resistance. The kinase inhibitors gefitinib and imatinib mesylate also interact with BCRP. Gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, inhibits its transporter function and reverses BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transfected human epidermoid carcinoma A431 cells and BCRP-transfected human non-small cell lung cancer PC-9 cells show gefitinib resistance. Imatinib, an inhibitor of BCR-ABL tyrosine kinase, also inhibits BCRP-mediated drug transport. Hence, both functional SNPs and inhibitors of BCRP reduce its transporter function and thus modulate substrate pharmacokinetics and pharmacodynamics.

Original languageEnglish
Pages (from-to)73-80
Number of pages8
JournalCancer Letters
Volume234
Issue number1
DOIs
Publication statusPublished - 2006 Mar 8

Fingerprint

Therapeutic Uses
Single Nucleotide Polymorphism
Breast Neoplasms
Proteins
Drug Resistance
Estrogens
Antineoplastic Agents
irinotecan
Protein-Tyrosine Kinases
Topotecan
Phytoestrogens
Mitoxantrone
ATP-Binding Cassette Transporters
Terminator Codon
Estrone
Protein Transport
Tamoxifen
Epidermal Growth Factor Receptor
Flavonoids
Non-Small Cell Lung Carcinoma

Keywords

  • ABC transporter
  • ABCG2
  • Drug resistance

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Biology
  • Oncology

Cite this

Functional SNPs of the breast cancer resistance protein - Therapeutic effects and inhibitor development. / Yanase, Kae; Tsukahara, Satomi; Mitsuhashi, Junko; Sugimoto, Yoshikazu.

In: Cancer Letters, Vol. 234, No. 1, 08.03.2006, p. 73-80.

Research output: Contribution to journalArticle

Yanase, Kae ; Tsukahara, Satomi ; Mitsuhashi, Junko ; Sugimoto, Yoshikazu. / Functional SNPs of the breast cancer resistance protein - Therapeutic effects and inhibitor development. In: Cancer Letters. 2006 ; Vol. 234, No. 1. pp. 73-80.
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