title: The effects of Tamoxifen and fish oil on mammary carcinogenesis in polyoma middle T transgenic mice.
abstract: In these experiments, we tested the hypothesis that inhibition of the estrogen receptor (ER) with Tamoxifen and activation of PPARγ with fish oil (FO) rich in omega-3 (n-3; known PPAR agonists) inhibit the development of hormone-independent breast cancer in view of the known crosstalk between the ER and PPARγ pathways. We selected the polyoma middle T transgenic mouse model, since in this system the development of ER- tumors is preceded by ER positive preneoplastic lesions. Tamoxifen admixed with a 20% corn oil (CO) modified AIN-76A diet delayed mammary carcinogenesis and inhibited tumor multiplicity, volume, and weight in a dose-dependent (1, 10, and 100 ppm) fashion. Administration of increasing concentrations of FO in the diet (5%, 10%, and 17%) did not affect any of the tumor parameters. Combined administration of different doses of Tamoxifen and FO delayed carcinogenesis and suppressed tumor multiplicity and volume to the same extent as Tamoxifen alone. Mice fed 10% FO exhibited the expected increase in n-3/n-6 ratio in plasma and tumor based on diet analysis. Further increase in the n-3/n-6 ratio was not observed in mice fed the 17% FO diet. FO reduced tissue levels of arachidonic acid and its metabolite PGF-2α. Our results support the role of ER expression by preneoplastic lesions in the development of hormone-independent tumors and consequently the importance of including ER targeting in combination with mechanistically based novel chemopreventive agents.
authors.affiliation: Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA. amanni@hmc.psu.edu
authors.forename: Andrea
authors.initials: A
authors.lastname: Manni
authors.forename: Haifang
authors.initials: H
authors.lastname: Xu
authors.forename: Sharlene
authors.initials: S
authors.lastname: Washington
authors.forename: Cesar
authors.initials: C
authors.lastname: Aliaga
authors.forename: Arunangshu
authors.initials: A
authors.lastname: Das
authors.forename: Timothy
authors.initials: T
authors.lastname: Cooper
authors.forename: John P
authors.initials: JP
authors.lastname: Richie
authors.forename: Bogdan
authors.initials: B
authors.lastname: Prokopczyk
authors.forename: Ana
authors.initials: A
authors.lastname: Calcagnotto
authors.forename: Neil
authors.initials: N
authors.lastname: Trushin
authors.forename: John P
authors.initials: JP
authors.lastname: Van den Heuvel
authors.forename: Christopher
authors.initials: C
authors.lastname: Hamilton
authors.forename: Laurence M
authors.initials: LM
authors.lastname: Demers
authors.forename: Jason
authors.initials: J
authors.lastname: Liao
authors.forename: Michael F
authors.initials: MF
authors.lastname: Verderame
authors.forename: Karam
authors.initials: K
authors.lastname: El-Bayoumy
mesh_terms: D000818:Animals; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D005260:Female; D005395:Fish Oils / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000037:antagonists & inhibitors*; D011120:Polyomavirus; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology*; D014412:Tumor Virus Infections
chemical_list: D047628:Estrogen Receptor alpha; D005395:Fish Oils; D047495:PPAR gamma; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen