title: A model of secreting murine mammary epithelial HC11 cells comprising endogenous Bcrp/Abcg2 expression and function.
abstract: Breast cancer resistance protein (Bcrp/Abcg2) and multidrug transporter 1 (Mdr1/Abcb1) are efflux proteins located in the apical membrane of mammary epithelial cells (MEC). Bcrp is induced in MEC during gestation and lactation, while Mdr1 is down-regulated during lactation. Numerous drugs and toxic compounds are known to be actively secreted into milk by Bcrp, but most chemicals have not been investigated in this respect, emphasizing the need for functional Bcrp studies in an established cell line with secreting mammary epithelial cells. The present study was undertaken to examine expressions of Bcrp and Mdr1 in mammary epithelial HC11 cells, derived from a mid-gestational murine mammary gland. In addition, Bcrp function was assessed by transport experiments with mitoxantrone (MX) in undifferentiated HC11 cells, in HC11 cells subjected to Bcrp RNA interference (RNAi), as well as in HC11 cells stimulated to differentiate by treatment with lactogenic hormones. Differentiated HC11 cells organized into alveolar-resembling structures and gene expression of the major milk protein β-casein was induced, whereas undifferentiated cells formed monolayers with lower β-casein expression. Bcrp and Mdr1 gene and protein were expressed in both undifferentiated and differentiated HC11 cells. Differentiation of HC11 cells resulted in increased Bcrp protein expression, while Mdr1 gene and protein expressions were reduced. The Bcrp inhibitor elacridar (GF120918) reduced secretion and increased accumulation of MX in both undifferentiated and differentiated HC11 cells. Silencing of the Bcrp gene caused an increased accumulation of MX. The results indicate that the HC11 cell model provides a promising tool to investigate transport of potential Bcrp substrates in mammary epithelial cells.
authors: Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 750 07, Uppsala, Sweden, Jonas.Tallkvist@slu.se.
authors: Jonas
authors: J
authors: Tallkvist
authors: Yagmur
authors: Y
authors: Yagdiran
authors: Louise
authors: L
authors: Danielsson
authors: Agneta
authors: A
authors: Oskarsson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D002364:Caseins / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006854:Hydrocortisone / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008942:Mitoxantrone / Q000494:pharmacology; D008954:Models, Biological; D011388:Prolactin / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000166:Acridines; D000970:Antineoplastic Agents; D002364:Caseins; D034741:RNA, Small Interfering; D044005:Tetrahydroisoquinolines; D011388:Prolactin; D008942:Mitoxantrone; C083501:Elacridar; D006854:Hydrocortisone