Breast cancer resistance protein family

The breast cancer resistance protein (BCRP) belongs to the G-branch of the ABC-transporter family (ABCG2). In contrast to most other ABC-proteins, BCRP consists of only one transmembrane domain (TDM) with one nucleotide binding fold (NBF) at its C-terminus. Because of this structural characteristic BCRP as well as other ABC-transporters with only one TMD are termed half transporters. To achieve functional activity these transporters have to form hetero- or homodimers. BCRP is involved in the multidrug resistance of certain tumors and transports endogenous compounds like cholesterol and steroid hormones. 

Members of the ABC family, which are involved in the cellular export of drugs, comprise multidrug resistance (MDR) 1/P-glycoprotein, the multidrug resistance associated proteins (MRP), and breast cancer resistance protein (BCRP). 

Multidrug resistance is observed in tumor cell populations exposed to anthracyclines. Attempts to reverse or prevent the emergence of resistance through the simultaneous use of inhibitors of P-glycoprotein, such as Ca channel blockers, steroidal compounds, and others, have yielded inconclusive results, primarily because of the effects of these inhibitors on anthracycline pharmacokinetics and metabolism. Anthracyclines also are exported from tumor cells by members of the MRP transporter family and by the breast cancer resistance protein. Other biochemical changes in resistant cells include increased glutathione peroxidase activity, decreased activity or mutation of topoisomerase II, and enhanced ability to repair DNA strand breaks. 

Recent evidence suggests that excretion of ochratoxin A into human milk is mediated by breast cancer resistance protein (BCRP). BCRP is a member of the ATP-dependent efflux transporter family, which is highly expressed during lactation in various species, including humans, and is known to be responsible for the excretion of various drugs and xenobiotics into milk (Jonker et al., 2005 Schrickx... 

ABC, ATP-binding cassette transporter superfamily ASBT, apical sodium-dependent bile salt transporter BCRP, breast cancer resistance protein BSEP, bile salt export pump MDRl, multidrug resistance MRR multidrug resistance-related protein NTCP, sodium taurocholate cotransporting polypeptide OAT, organic anion transporter OCT, organic cation transporter SLC, solute-linked carrier transporter family SLCO, solute-linked carrier organic anion transporter family. 

Diah, S.K., Smitherman, P.K., Aldridge, f., Volk, E.L., Schneider, E., Townsend, A.f. et al. (2001) Resistance to mitoxantrone in multidrug-resistant MCE7 breast cancer cells evaluation of mitoxantrone transport and the role of multidmg resistance protein family proteins. Cancer Research, 61 (14), 5461-5467. 

TRASTUZUMAB Trastuzumab (herceptin) targets the HER2/neu (ErbB-2) member of the EGE family of protein tyrosine kinase receptors. Activation of HER2/neu enhances metastatic potential and inhibits apoptosis. HER2/neu is overexpressed in up to 30% of breast cancers and is associated with clinical resistance to cytotoxic and hormone therapy. Trastuzumab can initiate Fcy-receptor-mediated ADCC and directly induce apoptosis. 

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