TY - JOUR
T1 - The Effects of Tamoxifen and Fish Oil on Mammary Carcinogenesis in Polyoma Middle T Transgenic Mice
AU - Manni, Andrea
AU - Xu, Haifang
AU - Washington, Sharlene
AU - Aliaga, Cesar
AU - Das, Arunangshu
AU - Cooper, Timothy
AU - Richie, John P.
AU - Prokopczyk, Bogdan
AU - Calcagnotto, Ana
AU - Trushin, Neil
AU - Van den Heuvel, John P.
AU - Hamilton, Christopher
AU - Demers, Laurence M.
AU - Liao, Jason
AU - Verderame, Michael F.
AU - El-Bayoumy, Karam
N1 - Funding Information:
Acknowledgments This work is supported by grant KG081632 from Susan G. Komen for the Cure.
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
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U2 - 10.1007/s12672-011-0078-2
DO - 10.1007/s12672-011-0078-2
M3 - Article
C2 - 21769696
AN - SCOPUS:79960959565
SN - 1868-8497
VL - 2
SP - 249
EP - 259
JO - Hormones and Cancer
JF - Hormones and Cancer
IS - 4
ER -