title: Lack of ABCG2 shortens latency of BRCA1-deficient mammary tumors and this is not affected by genistein or resveratrol.
abstract: In addition to their role in drug resistance, the ATP-binding cassette (ABC) transporters ABCG2 and ABCB1 have been suggested to protect cells from a broad range of substances that may foster tumorigenesis. Phytoestrogens or their metabolites are substrates of these transporters and the influence of these compounds on breast cancer development is controversial. Estrogen-like properties might accelerate tumorigenesis on the one hand, whereas their proposed health-protective properties might antagonize tumorigenesis on the other. To address this issue, we used a newer generation mouse model of BRCA1-mutated breast cancer and examined tumor latency in K14cre;Brca1(F/F); p53(F/F), Abcb1a/b(-/-);K14cre;Brca1(F/F); p53(F/F), or Abcg2(-/-);K14cre;Brca1(F/F); p53(F/F) animals, fed with genistein- or resveratrol-supplemented diets. Ovariectomized K14cre;Brca1(F/F); p53(F/F) animals were included to evaluate whether any estrogen-mimicking effects can restore mammary tumor development in the absence of endogenous estrogens. Compared with the ABC transporter proficient model, ABCG2-deficient animals showed a reduced median tumor latency of 17.5 days (P < 0.001), whereas no significant difference was observed for ABCB1-deficient animals. Neither genistein nor resveratrol altered this latency reduction in Abcg2(-/-);K14cre;Brca1(F/F); p53(F/F) animals. Ovariectomy resulted in nearly complete loss of mammary tumor development, which was not restored by genistein or resveratrol. Our results show that ABCG2 contributes to the protection of genetically instable epithelial cells against carcinogenesis. Diets containing high levels of genistein or resveratrol had no effect on mammary tumorigenesis, whether mice were lacking ABCG2 or not. Because genistein and resveratrol only delayed skin tumor development of ovariectomized animals, we conclude that these phytoestrogens are no effective modulators of mammary tumor development in our mouse model.
authors: Division of Molecular Oncology, The Netherlands Cancer Institute (Antoni van Leeuwenhoek Hospital), Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors: Serge A L
authors: SA
authors: Zander
authors: Ariena
authors: A
authors: Kersbergen
authors: Wendy
authors: W
authors: Sol
authors: Maaike
authors: M
authors: Gonggrijp
authors: Koen
authors: K
authors: van de Wetering
authors: Jos
authors: J
authors: Jonkers
authors: Piet
authors: P
authors: Borst
authors: Sven
authors: S
authors: Rottenberg
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D005260:Female; D019833:Genistein / Q000008:administration & dosage*; D015674:Mammary Neoplasms, Animal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010052:Ovariectomy; D048789:Phytoestrogens / Q000008:administration & dosage; D000077185:Resveratrol; D013267:Stilbenes / Q000008:administration & dosage*; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; 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; D000975:Antioxidants; D019313:BRCA1 Protein; D048789:Phytoestrogens; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D019833:Genistein; C507084:Abcb1b protein, mouse; D000077185:Resveratrol