Progesterone-Independent Effects of Human Progesterone Receptors (PRs) in Estrogen Receptor-Positive Breast Cancer: PR Isoform-Specific Gene Regulation and Tumor Biology

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2005-03, Vol.19 (3), p.574-587
• Main Authors: Jacobsen, Britta M, Schittone, Stephanie A, Richer, Jennifer K, Horwitz, Kathryn B
• Format: Article
• Language: English
• Subjects: Apoptosis; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Adhesion; Cell Line, Tumor; Cell Movement; Female; Gene Expression Profiling; Gene Expression Regulation; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Immunohistochemistry; Ligands; Microscopy, Confocal; Neoplasm Metastasis; Neoplasms - metabolism; Paclitaxel - pharmacology; Progesterone - metabolism; Promoter Regions, Genetic; Protein Isoforms; Receptors, Estrogen - metabolism; Receptors, Progesterone - chemistry; Receptors, Progesterone - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; Time Factors; Transcription, Genetic
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0287

Progesterone receptors (PRs) are prognostic markers in breast cancers irrespective of the patient’s progestational status. However, there are two PR isoforms, PR-A and PR-B, that are equimolar in the normal breast but dysregulated in advanced disease. Postmenopausal, tamoxifen-treated patients with estrogen receptor (ER)-positive, PR-A-rich tumors have much faster disease recurrence than patients with PR-B-rich tumors. To study the mechanisms we engineered ER+ breast cancer cells that express each PR isoform under control of an inducible promoter. We identified 79 genes regulated by progesterone (P), mainly by PR-B, and 51 genes regulated without progesterone, mainly by PR-A. Only nine genes were regulated with and without ligand, leading to definition of three classes: I) genes regulated only by liganded PR; II) genes regulated only by unliganded PR; III) genes regulated by both. Unliganded PR-A and PR-B differentially regulate genes that coordinate extracellular signaling pathways and influence tumor cell biology. Indeed, in the absence of P, compared with ER+/PR-B+ or PR− cells, ER+, PR-A+ cells exhibit an aggressive phenotype, are more adhesive to an extracellular matrix, and are more migratory. Additionally, unliganded PR-A and PR-B both inhibit cell growth and provoke resistance to Taxol-induced apoptosis. We propose that PR-A:PR-B ratios, even in the absence of P, influence the biology and treatment response of ER+ tumors, that PR-A isoforms are functionally dominant in P-deficient states, and that PR-A rich tumors are especially aggressive.