Abstract Purpose: We examined Estrogen receptor (ER) mRNA expression and molecular subtypes in breast cancers that are Progesterone receptor (PR) positive but ER negative by immunohistochemistry (IHC) to assess if these cancers molecularly resemble true ER positive cancers. Patients and Methods: Patients were those with newly diagnosed ERBB2-negative breast cancer treated with neoadjuvant chemotherapy containing sequential taxane and antheracycline-based regimens (then endocrine therapy if ER-positive by IHC). ER and PR status was determined by IHC in 501 primary breast cancers in routine pathology laboratory. Gene expression profiling was done with the Affymetrix U133A gene chip (Gene Expression Omnibus number: GSE25066). We compared expressions of ESR1, MKI67 mRNA and molecular subtypes determined by the PAM 50 classifier between IHC-ER-positive/PR-positive (n = 223), ER-positive/PR-negative (n = 73), ER-negative/PR-positive (n = 20), and ER-negative/PR-negative (n = 185) cancers. We also plotted survival curves by ER and PR status based on IHC. Results: ER or PR positivity by IHC was defined ≥ 1% staining. ER positivity by ESR1 mRNA expression was defined as > 10.18 previously published. Among the IHC-ER-negative/PR-positive, ER-positive/PR-negative, and both ER/PR-positive, and ER/PR-negative patients, 25%, 79%, 96% and 12% were positive by ESR1 mRNA expression, respectively. The average ESR1 expression was significantly higher in the ER/PR-positive and ER-positive/PR-negative cohorts compared with the ER-negative/PR-positive or ER/PR-negative cohorts. The average MKI67 mRNA expression was significantly higher in the ER-negative/PR-positive and ER/PR-negative cohorts. Among the ER-negative/PR-positive patients, 15% were luminal A, 5% were Luminal B, and 65% were basal like; among the ER-positive/PR-negative patients, 59% were luminal type. The relapse free survival rate of ER-negative/PR-positive patients was equivalent to ER/PR-positive or ER-positive/PR-negative, and significantly better than that of the ER-negative/PR-negative cohort. Conclusion: Only 20-25% of the ER-negative/PR-positive tumors show molecular features of ER-positive cancers (i.e high ER mRNA expression and luminal molecular class). These cancers also have higher proliferation rate than ER-positive cancer. However, the survival of these cancers with only chemotherapy is similar to ER-positive cancers with chemotherapy and endocrine therapy, and is better than ER-negative cancers. The contribution of endocrine therapy to this good outcome is to be invested in the future. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-09.