Effect of overexpression of progesterone receptor A on endogenous progestin-sensitive endpoints in breast cancer cells

The human progesterone receptor (PR) is expressed as two isoforms, PRA and PRE, which differ in the N-terminal region and exhibit different activities in vitro, with PRA demonstrating dominant negative inhibitory effects on t he activity of PRE and other nuclear receptors. PRA and PRE are expressed i n target tissues at comparable levels although cells expressing a predomina nce of one isoform can be identified. In breast cancers, PRA is expressed a t high levels in some tumors, and this may be associated with features of p oorer prognosis. To investigate the role of PRA overexpression in PR-positi ve target cells, the effect of PRA induction on cell proliferation and expr ession of endogenous progestin-sensitive genes, SOX4 and fatty acid synthet ase (FAS), was examined using PR-positive T-47D cell lines, which express a predominance of PRE, in which PRA could be increased 2- to 20-fold over ba sal levels. No effect of PRA induction was noted on cell proliferation, but marked changes in morphology, consistent with loss of adherent properties, were observed. Increases up to 4-fold in the relative PRA levels augmented progestin induction of SOX4 mRNA expression, and RU486 treatment revealed a progestin agonist effect. There was no consistent effect of PRA induction on progestin-mediated increases in FAS mRNA levels under these conditions. Clones with PRA:PRB ratios greater than 15 were associated with diminished progestin responses on both SOX4 and FAS mRNA expression. These data show that PRA overexpression is associated with alteration in adhesive propertie s in breast cancer cells and effects on endogenous progestin targets that w ere dependent on the cellular ratio of PRA:PRB. The results of this study a re consistent with the view that PRA expression can fluctuate within a broa d range in target cells without influencing the nature of progestin action on downstream targets, but that overexpression of PRA, such as is seen in a proportion of breast cancers, may be associated with inhibition of progest in action and features of poor prognosis.