Enhanced Progesterone Receptor A expression by dietary soy in a hormone-dependent (NMU) model of rat mammary carcinogenesis: implications for tumor progression.

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In previous work, we showed that lifetime exposure of Sprague-Dawley rats to AIN-93G diet made with soy protein isolate (SPI) as sole protein source, protected against NMU-induced mammary tumorigenesis, relative to the control (Casein, CAS) diet. The reduction in mammary tumor incidence (by 20%) with dietary SPI mimics the low breast cancer incidence in women with high dietary intake of soy foods. Interestingly, in SPI-fed rats that developed mammary tumors, a higher percentage of tumors with infiltrating ductal carcinoma (IDC) than ductal carcinoma in situ (DCIS) was observed, when compared to tumors of the CAS group, suggesting potential effects of soy components on tumor progression. Given the reported inverse correlation between serum progesterone (P) levels and breast cancer risk in premenopausal women; the increased progesterone receptor (PR) expression in mammary tissue of women consuming dietary soy supplement; and the decreased P levels in women on soy-based diets, we evaluated the expression of PR-A and PR-B isoforms in pathologically normal (designated normal) mammary glands and corresponding mammary tumors (IDC+DCIS), and serum P levels of NMU-exposed rats fed CAS or SPI. Transcript levels for PR-A were higher in normal mammary glands for the SPI than for the CAS group, while those for PR-B did not differ with diet. The ratio of PR-A/PR-B was four-fold higher for the SPI relative to the CAS group in normal mammary glands, but was not different in tumor tissues. The increased PR-A/PR-B ratio with SPI was accompanied by increased levels of HER-2/neu oncogene, whose up-regulated expression is reported in invasive breast cancers. Antibody against PR-A/B proteins demonstrated nuclear PR expression in normal mammary glands and mammary tumors, while antibody specific to PR-B showed negligible expression of this PR isoform. Serum P levels were lower (P<0.01) in tumor-bearing rats fed SPI than those fed CAS, with no differences (P=0.259) noted for serum estrogen. Since breast cancer patients with mammary PR-A greater than PR-B expression were found to be less responsive to endocrine therapy than those with higher PR-B expression, our findings of increased expression of PR-A with dietary soy in rats with NMU-induced tumors may have important implications for women with benign or malignant breast cancer consuming soy-based diets. (Supported by USDA-CRIS-6251-51000-005-02S).