Study summary: The current study was designed to examine serum progesterone levels and progesterone receptor expression in normal mammary glands and corresponding mammary tumors in rats fed a soy protein isolate or casein diet (control diet). Previously, the authors showed that lifetime exposure of Sprague-Dawley rats to a diet made with soy protein isolate as the only protein source protected against chemically-induced mammary tumorigenesis, relative to the control (casein) diet. However, in the soy protein isolate-fed rats that developed tumors, there was a higher proportion of tumors with infiltrating ductal carcinoma (IDC) than with ductal carcinoma in situ (DCIS), compared to the tumors of the casein-fed rats. This suggests potential unfavorable effects of soy components on tumor progression. The present study focused on progesterone. An inverse associated between serum progesterone levels and breast cancer risk has been reported in premenopausal women. Also, the breast tissue of women consuming dietary soy supplements has been reported to have increased progesterone receptor (PR) expression, whereas the breast tissue of women on soy-based diets has been found to be decreased. In the study, the expression of progesterone receptor A (PR-A) and progesterone receptor B (PR-B) isoforms in pathologically normal mammary glands and corresponding mammary tumors (IDC and DCIS) were evaluated. In addition, the serum progesterone levels of rats fed soy protein isolate or casein and exposed to the carcinogen N-nitroso-N-methylurea (NMU) were examined. PR-A levels were found to be higher in normal mammary glands in the soy protein isolate-fed rats than in the casein group, while PR-B levels did not differ with diet. The ratio of PR-A/PR-B was four-fold higher in the soy protein isolate relative to the casein group in normal mammary glands, but was not different in tumor tissues. The increased PR-A/PR-B ratio in the soy protein isolate group was accompanied by increased levels of HER-2/neu oncogene, whose up-regulated expression is reported in invasive breast cancers. Serum progesterone levels were found to be significantly lower (P<0.01) in tumor-bearing rats fed soy protein isolate than those fed casein, while no differences (P=0.259) were observed for serum estrogen. The authors comment that since breast cancer patients with mammary PR-A greater than PR-B expression have been found to be less responsive to endocrine therapy than those with higher PR-B expression, the finding 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.