Individual And Combined Effects Of Tamoxifen And Fish Oil On Mammary Carcinogenesis In Polyoma Middle T Transgenic Mice

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL There are currently no known effective regiments able to prevent the development of estrogen-receptor (ER) negative breast cancer in humans. We hypothesize that ER, frequently upregulated in preneoplastic mammary lesions, may contribute to the development of hormone-independent tumors through crosstalk with multiple cellular oncogenic pathways. Therefore, a multi-targeted approach is likely to be necessary to prevent ER negative tumors. In our previous study, we tested this hypothesis in CD rats and we showed that omega-3 rich fish oil (FO) potentiated the suppressive effect of Tamoxifen (Tam) on mammary carcinogenesis (A. Manni, et al. Cancer Prev Res 3:322, 2010). In the present investigations, we tested this hypothesis in polyoma middle T transgenic mice, since in this experimental system the development of ER negative tumors is preceded by preneoplastic lesions overexpressing functional ER, as evidenced by the concomitant upregulation of progesterone receptors which are products of estrogen action. Administration of increasing concentrations of Tam (1 ppm, 10 ppm, and 100 ppm) admixed with 20% corn oil (CO) modified AIN-76A diet, starting at 3 weeks of age, significantly delayed mammary carcinogenesis, inhibited tumor multiplicity by ∼50%, tumor volume by ∼90%, and tumor weight by ∼70% in a dose dependent fashion. At termination (week 12), however, tumor incidence was nearly 100% in all experimental groups. When Tam treatment was started after tumors had developed, no inhibition of tumor growth was observed, a finding consistent with the absence of ER in invasive adenocarcinomas in this experimental model. Administration of increasing concentrations of FO in the diet (5% FO + 15% CO; 10% FO + 10% CO, 17% FO + 3% CO) started at 3 weeks of age did not affect any of the tumor parameters compared to the control 20% CO diet. Combined administration of suboptimal (1 ppm) and optimal (100 ppm) doses of Tam with 17% FO and 10% FO respectively, delayed carcinogenesis and suppressed tumor multiplicity and volume to the same extent as observed with Tam alone. Therefore, the results indicate that, under these experimental conditions, FO failed to potentiate the chemopreventive action of Tam. Our results, however, provide support for the role of ER expression by the preneoplastic lesions in the development of hormone independent tumors and, consequently, for the importance of including ER targeting in combined chemoprevention strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3710. doi:10.1158/1538-7445.AM2011-3710