CHARACTERIZATION OF PROGESTERONE-RECEPTOR-A AND PROGESTERONE-RECEPTOR-B EXPRESSION IN HUMAN BREAST-CANCER

The human progesterone receptor (PR) is a ligand-activated nuclear tra nscription factor that mediates progesterone action in target tissues, Two PR proteins, PR-A (M(r) 81,000-83,000) and PR-B (M(r) 116,000-120 ,000), have been described and different physiological activities ascr ibed to each on the basis of in vitro studies, suggesting that their r atio of expression may control progesterone responsiveness in target c ells. Presence of PR in breast tumors is an important indicator of lik ely responsiveness to endocrine agents, However, the relative expressi on of PR-A and B in breast cancer has not been described, and its clin ical significance has not been addressed. Expression of PR-A and B was measured by immunoblot analysis of 202 PR-positive human breast tumor cytosols, The ratio of expression of the two PR proteins (PR-A/B) ran ged from 0.04 to 179.3. The median PR-A/B ratio was 1.26, and 61.4% of samples had PR-A/B ratios between 0 and 2. PR-A/B ratios deviated sig nificantly from a normal Log distribution; tumors containing a PR-A/B ratio greater than 4 were overrepresented in the group. Linear regress ion analysis revealed that high PR-A/B ratios, in general, derived fro m a low concentration of PR-B rather than high expression of PR-A, PR- A/B protein ratios were not correlated with the age of the patient or with total PR concentration. A third PR protein band (PR78kDa) was det ected in a number of samples and comprised greater than 20% of total P R protein in 52 (25.7%) of the 202 tumor samples examined. The range o r frequency distribution of PR-A/B ratios in samples containing PR78kD a was not different to the overall group. In summary, in PR-positive b reast tumors, the ratio of expression of PR-A and B proteins is close to unity, as is seen in a number of other progestin target tissues. Ho wever, a significant proportion of tumors expressed very Low levels of PR-B and a consequently high PR-A/B ratio. Although the clinical cons equence of this observation is not known, the in vitro findings that P R-A may act as a repressor of PR-B suggest that tumors containing prim arily PR-A may identify a subset of patients with low or aberrant resp onse to endocrine agents.