Why are there two progesterone receptors

Abstract This year represents the 20th anniversary of our first demonstration that human breast cancers contain progesterone receptors (PR), and are markers of hormone dependence. These receptors are now routinely measured in tumours not only as markers of hormone dependence, but of disease prognosis. Theoretically, their central function in breast cancers is not as markers, but as effectors of the proliferative signals of endogenous progesterone in premenopausal women, and as targets for progestins and antiprogestins. At present, PR are rarely measured for these functional purposes. The actions of PR are complex, and responsiveness to progestin agonists or antagonists will depend on the gene whose activity is being measured, the peculiarities of the cell and tissue under study, and most importantly, the PR isoform that predominates in a tissue or tumour. The differential expression of PR isoforms, serves, we believe, to fine-tune responsiveness to this important reproductive hormone. Knowledge, not just of the PR content of a tissue, but of the expression of B- vs Areceptors in that tissue, will be vital to understanding the effects of progestins therein. Recent studies with PR have forced us to revise the standard model of steroid receptor action. The conventional model, which depicts receptors as ligand-activated proteins that bind to specific DNA sequences at ‘consensus’ hormone response elements and activate transcription, is not incorrect. It is, however, oversimplified, as studies with PR demonstrate. These demands include requirements for both positive and negative transcriptional regulation; for tissue specificity of action; and for regulation of composite and simple gene promoters. Multiple functional domains control intramolecular contacts, intermolecular protein-protein interactions, and DNA binding. As steroid antagonists are synthetic rather than natural hormones, their binding produces structural alterations in the receptors that unveil additional novel interactive capabilities. While antiprogestins competitively inhibit agonists by forming non-productive receptor-DNA complexes, this is not their sole mechanism of action. Antiprogestin effects may also be mediated by receptor interactions with coactivators whose function is in turn controlled by non-steroidal signals. When two different signalling pathways are activated simultaneously they can cooperate to produce unintended effects. Additionally, it seems clear that antagonist-occupied receptors can act without binding to canonical PREs, or without binding to DNA at all, relying perhaps on tethering proteins. This may be a consequence of the unusual allosteric structure imparted on the receptors by synthetic ligands. For some of these unusual actions, the receptors may even be monomeric rather than dimeric. Investigators should not assume when studying antiprogestins that a specific mechanism is operating. These novel actions begin to explain two properties of steroid antagonists that have puzzled investigators. One is the common observation that antagonists are agonists in some normal tissues. The other, an extension of the first, is that in malignant cells, antagonists can acquire agonist-like properties as tumours progress, leading to treatment failure. Although such tumours are called ‘resistant’, they may in fact be responding quite well to the antagonist! With respect to receptor protein structure, we are only beginning to appreciate its complexity. For example, it appeared initially that the structural independence of functional domains permitted analysis of receptor fragments by fusing them to heterologous proteins. However, we now know that important functional domains can overlap; that other functional domains may be discontinuous; and that one domain can modulate the activity of another. This means that analysis of receptor fragments in chimeras is an incomplete test of domain function, and that we need innovative experimental strategies to understand this intramolecular cross-talk.