Abstract
Dietary contribution to breast cancer risk, recurrence, and progression remains incompletely understood. Increased consumption of soy and soy isoflavones is associated with reduced mammary cancer susceptibility in women and in rodent models of carcinogenesis. In rats treated with N-methyl-N-nitrosourea, dietary intake of soy protein isolate (SPI) reduced mammary tumor occurrence but increased incidence of more invasive tumors in tumored rats, relative to the control diet casein. Here we evaluated whether mammary tumor progression in tumor-bearing rats lifetime exposed to SPI is associated with deregulated progesterone receptor (PR) isoform expression. In histologically normal mammary glands of rats with invasive ductal carcinoma lesions, PR-A protein levels were higher for SPI- than casein-fed rats, whereas PR-B was undetectable for both groups. Increased mammary PR-A expression was associated with higher transforming growth factor-β1, stanniocalcin-1, and CD44 transcript levels; lower E-cadherin and estrogen receptor-α expression; and reduced apoptotic status in ductal epithelium. Serum progesterone (ng/ml) (CAS: 25.94 ± 3.81; SPI: 13.19 ± 2.32) and estradiol (pg/ml) (CAS: 27.9 ± 4.49; SPI: 68.48 ± 23.87) levels differed with diet. However, sera from rats of both diet groups displayed comparable mammosphere-forming efficiency in human MCF-7 cells. Thus, soy-rich diets may influence the development of more aggressive tumors by enhancing PR-A-dependent signaling in premalignant breast tissues.
ACKNOWLEDGMENTS
The authors thank Dr. Frank A. Simmen (UAMS) for helpful discussion during the course of the study and S. Renee Till for assistance with immunohistochemistry. This study was supported by grants from the USDA-CRIS-6251-5100002-06S to the Arkansas Children's Nutrition Center and the Children's University Medical Group of the Arkansas Children's Hospital Research Institute (RCM Simmen).