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 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.
McGowan
E M
EM
Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, New South Wales, Australia.
Clarke
C L
CL
D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D002455:Cell Division; D064429:Fatty Acid Synthases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D010957:Plasmids; D011372:Progestins / Q000378:metabolism* / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D055751:SOXC Transcription Factors; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D006609:High Mobility Group Proteins; D011372:Progestins; D011980:Receptors, Progesterone; C083431:SOX4 protein, human; D055751:SOXC Transcription Factors; D015534:Trans-Activators; C101118:progesterone receptor A; D007544:Isopropyl Thiogalactoside; D064429:Fatty Acid Synthases