Breast Cancer Patients with Progesterone Receptor PR-A-Rich Tumors Have Poorer Disease-Free Survival Rates

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Abstract
Purpose: No study has yet analyzed whether changes in relative expression levels of progesterone receptor (PR) isoforms A and B in human breast tumors have significance in predicting clinical outcome. Human PRs are ligand-activated nuclear transcription factors that mediate progesterone action. Their presence in breast tumors is used to predict functional estrogen receptors (ERs) and, therefore, also to predict the likelihood of response to endocrine therapies and disease prognosis. The two PR isoforms, PR-A and PR-B, possess different in vitro and in vivo activities, suggesting that in tumors, the ratio of their expression may control hormone responsiveness. In general, PR-B are strong transcriptional activators, whereas PR-A can act as dominant repressors of PR-B and ER. Thus their balance may affect tamoxifen response in breast cancers. Experimental Design: To determine whether differential expression of the PR isoforms is associated with clinical outcome and hormonal responsiveness, PR-A and PR-B were measured by immunoblot analysis of cell lysates from 297 axillary node-positive breast tumors. Results: Expression of the two isoforms correlated with each other, as well as with ER. Additional analyses revealed that patients with PR-positive tumors but high PR-A:PR-B ratios, which were often caused by high PR-A levels, were 2.76 times more likely to relapse than patients with lower ratios, indicating resistance to tamoxifen. Conclusions: This study suggests that knowledge of the PR-A:PR-B ratio may identify a subgroup of ER-positive/PR-positive patients with node-positive breast cancer that benefit poorly from endocrine therapy.

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