Role of Protein Synthesis Initiation Factors in Dietary Soy Isoflavone-Mediated Effects on Breast Cancer Progression

Abstract

Abstract : The role of dietary soy in breast cancer has been the subject of intense investigation and is thought to be cancer preventive. However, the beneficial effects of soy on established breast cancer is controversial. The goal of this research is to investigate the potential molecular mechanisms by which soy isoflavones affect established breast cancers. A previous study by our laboratory reported that dietary genistein reduced tumor growth and metastasis and down regulated cancer promoting genes in a nude mouse model with tumors established from MDA-MB-435 metastatic cancer cells. In contrast, daidzein increased primary ammary tumor growth and metastasis, and significantly upregulated genes that regulate proliferation and protein synthesis including eukaryotic initiation factor eIF4F members. Our hypothesis is that soy isoflavones modulate breast cancer progression by specific regulation of the eIF4F eukaryotic initiation factor complex to affect the synthesis of cancer regulatory proteins. We have reported that equol, a metabolite of the soy isoflavone daidzein, may advance breast cancer progression via upregulation of the eukaryotic initiation factor eIF4G. In estrogen receptor (-) metastatic breast cancer cells, elevated eIF4G levels in response to equol were associated with an increase in cell viability and the translation of specific mRNAs with internal ribosome entry sites (IRES) including the transcription factor c-Myc, a central regulator of cancer malignancy. Herein, we show that eIF4G knockdown results in a marked reduction of the equol-mediated increase in protein synthesis initiation of specific IRES-dependent pro-cancer molecules, without affecting the increases in c-Myc levels and cell viability. Knockdown of c-Myc abrogated the increased cell viability in response to equol. Our findings implicate c-Myc and eIF4G in the cancer promoting effects of equol in metastatic breast cancer via regulation of protein synthesis initiation of molecules that con