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.

Administration of omega-3 fatty acids and Raloxifene to women at high risk of breast cancer: interim feasibility and biomarkers analysis from a clinical trial

“…We believe that a major attractive feature of this approach is its safety since it allows us to combine a lower and hence less toxic dose of antiestrogens with n-3FA, compounds that are known to have inherent health benefits (that is, reduction in cardiovascular risk) beyond their potential chemopreventive benefit in breast cancer. 14 In parallel with our preclinical studies conducted in experimental models of mammary carcinogenesis, [2][3][4] we have recently initiated a randomized clinical trial in postmenopausal women (NCT00723398) testing the combined effects of Lovaza and Ral at half its conventional dose (that is, 30 vs 60 mg) in reducing breast density, a well-established risk factor for breast cancer. The effects of this treatment combination will be compared with that of Ral alone at its conventional dose of 60 mg daily.…”

“…1 While basic mechanisms are under investigation using preclinical models of mammary carcinogenesis, [2][3][4] we are testing concomitantly the clinical relevance of this approach in postmenopausal women using surrogate markers of breast cancer development (NCT00723398). While the primary end point of our clinical trial is a reduction in breast density, a wellestablished risk factor for breast cancer, 5 we are also examining the effects of the individual and combined administration of Ral and n-3FA on several biomarkers thought to be potentially involved in mammary carcinogenesis.…”

Natural Products for Cancer-Targeted Therapy: Citrus Flavonoids as Potent Chemopreventive Agents

“…Besides, estrogen-ER complex may interact with transcription factors, such as SP-1 (Meyer et al, 2006). So, ER targeting could be an approach of both chemoprevention and cancer targeted therapy (Manni et al, 2011). Compounds possessing similar effect to estrogen is called to have estrogenic effect, and numerous biocompounds have been shown to be active as phytoestrogens.…”

Fish Oil Enhances T Cell Function and Tumor Infiltration and Is Correlated With a Cancer Prevention Effect in HER-2/neu But Not PyMT Transgenic Mice

“…Food intake was monitored and food was replaced every 2-3 days. Food intake, body weight, and tumor size were monitored as previously reported (19). At termination, tumors were removed and their volume was determined using the formula V D (width £ 2 £ length £ p)/6.…”

“…The HER-2/ neu transgenic mouse model was selected because FO supplementation has a cancer prevention effect, with increased tumor latency and decreased tumor multiplicity (18). In contrast, n-3 PUFAs have no cancer prevention effect in the PyMT model due to, in part, a lack of effect of FO on the expression of PPAR-related genes (19). Thus, the HER-2/neu and PyMT models were used to compare and contrast the immunoregulatory role of PUFAs in model systems that have differential cancer prevention responsiveness to FO supplementation in an effort to better understand the relationship between fish oil, immune regulation and mammary carcinogenesis.…”