Characterization of progesterone receptor isoform-selective activities of progesterone receptor modulators in breast cancer cells.

• Main Author: Leo, Joyce Ching Li.
• Other Authors: Lin, Valerie Chun Ling
• Format: Theses and Dissertations
• Published: 2008
• Subjects: DRNTU::Science::Biological sciences
• Online Access: http://hdl.handle.net/10356/6571
• Institution: Nanyang Technological University

This study reveals the effects of progesterone receptor modulators (PRMs) mediated by PR isoforms in PR-transfected MDA-MB-231 cells. Through PR-A and PR-B, PRMs CP8668, AED and Dex-Mes exhibited progesterone agonist effect in which they induced cell spreading, focal adhesion, cell migration and inhibited cell cycle progression. Although an antiprogestin, RU486 along with PRMs CDB4124, 17a-hydroxy CDB4124 and VA2914 demonstrated progesterone agonist effect in cells transfected with PR-B. Nonetheless, these compounds modulated the cellular activity of PR-A in an activity-dependent manner; antiprogestins displayed antagonist effects on cell morphology, focal adhesion and cell migration but showed progesterone agonist effect by inhibiting cell growth. These observations were consistent with the gene expression study at the cellular level. This study suggest that the effects of PRMs is pathway-selective: antiprogestins mediated growth-inhibitory effect through both PR-A and PR-B but antiprogestins mediated distinct effects on cell morphology, focal adhesion and the expression of cell adhesion genes in cells expressing either PR-A or PR-B. Moreover, findings in this study imply that the functional difference between PR-A and PR-B are PR ligand-dependent. Besides providing a cell model to study the functional variation of the two PR isoforms, PR-transfected MDA-MB-231 cells may be used to identify the agonist or antagonist nature of PRM based on cell morphological appearance.