The long-term goal of this SC3 award (from 2008-2022), is to investigate the effect of natural and experimental therapeutics on breast cancer metastasis. Our objective from 2008-2018 was to investigate the molecular mechanisms by which dietary polyphenols affect established breast cancer and examine a metastasis preventive or promoting role for dietary plant-derived compounds. The data generated during the first SC3 award (2008-2012) resulted in six peer- reviewed publications that demonstrated a metastasis preventive role for red wine polyphenols and a promoting role for soy isoflavones. During the second phase of this award (2013-2017), we reported that the soy isoflavone genistein is metastasis preventive while daidzein or combined soy isoflavones genistein, daidzein, and glycitein (in the ratio found in soy foods) increases tumor growth, metastasis, and expression of eukaryotic protein synthesis initiation factors, eIF4E and eIF4G. In vitro, the effects of the daidzein metabolite equol on upregulation of eIF4G and metastatic cancer cell proliferation were analogous to the daidzein effects in vivo. We published five more journal articles on the mechanism of metastasis prevention by genistein and the consequences of the increased eIF4G levels by equol. Equol preferentially increases the synthesis of proteins that regulate tumor growth metastasis, and angiogenesis via its effects on eIF4G and the oncogenic transcription factor c-Myc. Therefore, we formulated the hypothesis that the in vivo pro-cancer effects of dietary daidzein are due to equol that is converted from daidzein by the gut microflora. To test this hypothesis, we generated a metastatic breast cancer cell line stably expressing a small interfering RNA (siRNA) directed at knocking down eIF4G expression, via an inducible Tetracycline promoter. These cell lines were used in vitro and in vivo to test the effect of equol on protein synthesis initiation and cancer progression. To validate a cancer promoting role for the daidzein metabolite equol in vivo, in September 2017, we initiated an experiment with immunocompromised mice bearing mammary fat pad tumors from control or eIF4G knockdown cells. Unfortunately, this study had to be abandoned due to the disruption caused by Hurricane Maria on 09/20/17. Therefore, this experiment needs to be repeated with larger mouse numbers and expanded treatments to obtain statistical power before a manuscript can be submitted for peer review and the graduate student can complete her Ph.D. Dissertation. In this administrative supplement, we are requesting funds to replace freezers, damaged due to power outages from Hurricanes Irma and Maria, and to replenish the thawed reagents and the immunocompromised mice that had to be sacrificed.
Metastatic disease when primary tumor cells establish secondary metastases at distant organs, complicates diagnosis and treatment, especially for breast cancer, where 30% of patients can have recurrent metastatic disease in bone, liver, and lung with a 5-year survival rate of 20%. Therefore, in this research we are investigating the relevance of dietary soy isoflavones in preventing or triggering metastasis. !
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