The human
progesterone receptor (PR) is expressed as two
isoforms, PRA and PRB, which differ in the N-terminal region and exhibit different activities in vitro, with PRA demonstrating dominant negative inhibitory effects on the activity of PRB and other
nuclear receptors. PRA and PRB are expressed in target tissues at comparable levels although cells expressing a predominance of one
isoform can be identified. In breast
cancers, PRA is expressed at high levels in some
tumors, and this may be associated with features of poorer prognosis. To investigate the role of PRA overexpression in PR-positive target cells, the effect of PRA induction on cell proliferation and expression of endogenous
progestin-sensitive genes, SOX4 and
fatty acid synthetase (FAS), was examined using PR-positive T-47D cell lines, which express a predominance of PRB, in which PRA could be increased 2- to 20-fold over basal 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 properties in
breast cancer cells and effects on endogenous
progestin targets that were dependent on the cellular ratio of PRA:PRB. The results of this study are consistent with the view that PRA expression can fluctuate within a broad 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
progestin action and features of poor prognosis.