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1. Zhonghua Zhong Liu Za Zhi. 2011 Sep;33(9):654-60.

[Regulation mechanism of breast cancer resistance protein by toremifene to
reverse BCRP-mediated multidrug resistance in breast cancer cells].

[Article in Chinese]

Zhang YH, Li G, Yu J, Xu MS, Liu ZX.

Department of Pathology, Beijing Tiantan Hospital, Capital Medical University,
Beijing 100050, China. Email: yuhuazhang111@yahoo.com.cn.

OBJECTIVE: To explore the regulation mechanism of the reversal of breast cancer
resistance protein-mediated multidrug resistance by toremifene.
METHODS: Two recombinant plasmids (pcDNA3-promoter-BCRP and pcDNA3-CMV-BCRP) were
designed to express the wild-type full-length BCRP cDNA enforced driven by its
endogenous promoter containing a functional ERE and a CMV promoter as control,
respectively. Two recombinant plasmids were transfected into ERα-positive MCF-7
and ERα-negative MDA-MB-231 breast cancer cell lines. Four kinds of BCRP
expressing cell lines of MCF-7/Promoter-BCRP, MCF-7/CMV-BCRP,
MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP were established in which BCRP
was promoted by the BCRP promoter and a CMV promoter as control, respectively.
The drug resistant cells were treated with toremifene. Then RT-PCR, Western blot,
mitoxantrone efflux assays and cytotoxicity assay were performed to detect the
reversal function of BCRP by toremifene on the drug resistance cell lines.
RESULTS: Toremifene significantly downregulated BCRP mRNA levels in a
dose-dependent manner in ERα-positive MCF-7/Promoter-BCRP cells than that of
untreated control cells. In MCF-7/Promoter-BCRP cells, toremifene at the dose of
0.1, 1 and 10 µmol/L decreased BCRP mRNA expression by 29.5% (P < 0.05), 68.1% (P
< 0.01) and 97.4% (P < 0.01), respectively. After being treated with toremifene
and 17β-estradiol, the BCRP mRNA level in MCF-7/Promoter-BCRP cells was 64.2% ±
1.3%, significantly higher than that of toremifene treatment control cells (3.8%
± 0.2%,P < 0.01). Furthermore, the effect of toremifene on BCRP protein is
similar in BCRP mRNA. Toremifene obviously increased the mitoxantrone
fluorescence intensity and decreased the efflux activity by 47.3% (P < 0.05) in
MCF-7/promoter-BCRP cells when compared with the untreated control, whereas
intracellular accumulation of mitoxantrone obviously decreased and the efflux
activity increased by 61.5% were observed in combination with 17β-estradiol when
compared with toremifene treatment alone. The results therefore suggested that
toremifene reversed mitoxantrone resistance in MCF-7/Promoter-BCRP cells.
However, in MCF-7/CMV-BCRP, MDA-MB-231/Promoter-BCRP and MDA-MB-231/CMV-BCRP
cells, toremifene or in combination with 17β-estradiol did not affect
intracellular mitoxantrone uptake.
CONCLUSION: Taken together, our findings indicate that expression of BCRP is
downregulated by toremifene, via a novel transcriptional mechanism which might be
involved in the ERE of BCRP promoter through ER-mediated to inactivate the
transcription of BCRP gene.

PMID: 22340044 [PubMed - in process]