Progesterone receptor (PR) function, while essential in normal human breast, is also implicated in
breast cancer risk. The two
progesterone receptors, PRA and PRB, are co-expressed at equivalent levels in normal breast, but early in
carcinogenesis normal levels of PRA:PRB are frequently disrupted, and predominance of one
isoform, usually PRA, results. In model systems, PRA and PRB have different activities, and altering the PRA:PRB ratio in cell lines alters PR signaling. The purpose of this study was to determine whether hormonal or reproductive factors contribute to imbalanced PRA:PRB expression in
breast tumors and the impact of PRA:PRB imbalance on disease outcome. The relative expression of PRA and PRB
proteins was determined by dual immunofluorescence histochemistry in archival
breast tumors and associations with clinical and reproductive history assessed. PRA:PRB expression was not influenced by reproductive factors, whereas exogenous
hormone use (menopausal
hormone treatment,
MHT) favored PRB expression (p < 0.035). The PRA:PRB ratio may be a discriminator of response to endocrine
therapy in the TransATAC sample collection, with high PRA:PRB ratio predicting earlier relapse for women on
tamoxifen, but not
anastrozole (mean lnPRA:PRB ratio; HR (95 % CI)
tamoxifen 2.45 (1.20-4.99); p value 0.02;
anastrozole 0.80 (0.36-1.78); p value 0.60). The results of this study show that PRA:PRB imbalance in breast
cancers is not associated with lifetime endogenous endocrine and reproductive factors, but is associated with
MHT use, and that PRA predominance can discriminate those women who will relapse earlier on
tamoxifen treatment. These data support a role for imbalanced PRA:PRB expression in
breast cancer progression and relative benefit from endocrine treatment.