The A and B isoforms of the human progesterone receptor operate through distinct signaling pathways within target cells.

manner. Analogous mutations, when introduced intohPR-A,haveno effect on itsability toinhibit thetranscriptional activity ofothersteroid hormonereceptors. Theobserved differences inthestructural requirements forhPR-BandhPR-Afunction suggest thattranscriptional activation andrepression byPRaremediated bytwoseparate pathways within the cell. Insupport ofthis hypothesis, we haveshownthat hPR-Amediated repression ofhumanestrogen receptor (hER)transcriptional activity isnotdependent on hERexpression level butdepends largely on theabsolute expression level ofhPR-A.Thus, itappearsthathPR-Ainhibits hERtranscriptional activity asa consequence ofa noncompetitive interaction ofhPR-Awitheither distinct cellular targets ordifferent contact sites on the same target. We proposethathPR-Aexpression facilitates a ligand-dependent cross-talk among sexsteroid receptor signaling pathways within thecell. Itislikely, therefore, thatalterations intheexpression level of hPR-Aoritscellular target canhaveprofound effects on thephysiological orpharmacological responsestosex steroid hormonereceptor ligands. Thegrowth anddevelopment ofthehumanmammary gland areregulated inpartbytheactions ofestrogen andprogesterone.Inthistissue, estrogen appearstohavea proliferative effect on mammary epithelial cells, whereasprogesterone functions asa modulator ofestrogen action (8). Themechanismbywhichprogesterone affects estrogen-stimulated responsesisunclear, thoughitsability tomodulate estrogen receptor (ER)expression islikely tobeimportant (8).In addition, accumulating evidence indicates thatprogestins can exhibit bothproliferative andantiproliferativ e activities on