title: Sterol transport by the human breast cancer resistance protein (ABCG2) expressed in Lactococcus lactis.
abstract: The human breast cancer resistance protein (BCRP, also know as ABCG2, MXR, or ABCP) is one of the more recently discovered ATP-binding cassette (ABC) transporters that confer resistance on cancer cells by mediating multidrug efflux. In the present study, we have obtained functional expression of human BCRP in the Gram-positive bacterium Lactococcus lactis. BCRP expression conferred multidrug resistance on the lactococcal cells, which was based on ATP-dependent drug extrusion. BCRP-mediated ATPase and drug transport activities were inhibited by the BCRP-specific modulator fumitremorgin C. To our knowledge these data represent the first example of the functional expression of a mammalian ABC half-transporter in bacteria. Although members of the ABCG subfamily (such as ABCG1 and ABCG5/8) have been implicated in the transport of sterols, such a role has not yet been established for BCRP. Interestingly, the BCRP-associated ATPase activity in L. lactis was significantly stimulated by (i) sterols including cholesterol and estradiol, (ii) natural steroids such as progesterone and testosterone, and (iii) the anti-estrogen anticancer drug tamoxifen. In addition, BCRP mediated the efflux of [3H]estradiol from lactococcal cells. Our findings suggest that BCRP may play a role in the transport of sterols in human, in addition to its ability to transport multiple drugs and toxins.
authors.affiliation: Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom.
authors.forename: Tavan
authors.initials: T
authors.lastname: Janvilisri
authors.forename: Henrietta
authors.initials: H
authors.lastname: Venter
authors.forename: Sanjay
authors.initials: S
authors.lastname: Shahi
authors.forename: Galya
authors.initials: G
authors.lastname: Reuter
authors.forename: Lekshmy
authors.initials: L
authors.lastname: Balakrishnan
authors.forename: Hendrik W
authors.initials: HW
authors.lastname: van Veen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics; D002784:Cholesterol / Q000493:pharmacokinetics; D004958:Estradiol / Q000493:pharmacokinetics; D015870:Gene Expression; D006801:Humans; D013294:Lactococcus lactis / Q000235:genetics; D009363:Neoplasm Proteins; D011374:Progesterone / Q000493:pharmacokinetics; D013261:Sterols / Q000493:pharmacokinetics*; D013629:Tamoxifen / Q000493:pharmacokinetics; D013739:Testosterone / Q000493:pharmacokinetics; D014316:Tritium
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D013261:Sterols; D013629:Tamoxifen; D014316:Tritium; D013739:Testosterone; D011374:Progesterone; D004958:Estradiol; D002784:Cholesterol