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.
Highlights
Several ATP-binding cassette (ABC) transporters act as cellular efflux pumps of drugs and cause multidrug resistance [1]
The latency in mammary tumor development is reduced in Abcg2À/À animals, but not in Abcb1a/bÀ/À animals
On the FVB/N background, we found that the median tumor latency of the K14cre; Brca1F/F;p53F/F females shortened from 213 to 201 days
Summary
Several ATP-binding cassette (ABC) transporters act as cellular efflux pumps of drugs and cause multidrug resistance [1]. They disrupted the Abcb1a gene and found decreased intestinal polyp and tumor incidence compared with Abcb1a wild-type mice, suggesting that P-gpmediated protection from xenotoxins allows epithelial cells with strong driver mutations to survive and progress into malignant tumors. This protective effect of P-gp may be specific for mice, as tumor-initiating cells of human colorectal tumors do not appear to be protected by ABCB1 [4]. These studies illustrate that we still do not fully understand what roles ABCB1 and ABCG2 play in protecting normal cells from carcinogenic xenobiotics
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
