ROLE OF ESTROGEN RECEPTOR BETA IN THE CONTROL OF HUMAN PROSTATE CANCER PROGRESSION

Background: Owing to the high incidence rate and the lack of effective treatments, androgen-independent prostate cancer (AIPC) is still a world-wide health problem in men. Thus, the identification of specific mechanisms contrasting PC growth and progression provides the rational for the development of new therapies for the advanced disease. A growing body of evidence suggests that the activation of estrogen receptor beta (ERbeta) protects epithelial cells from uncontrolled proliferation in many tumor models, including PC. By using high Gleason grade PC samples or the AIPC cell line DU145, recent evidences from our and other laboratories have indeed shown that ERbeta activation reduces cell proliferation, promotes apoptosis, maintains the epithelial phenotype and decreases cell migratory ability (likely through regulation of cell adhesion molecules); however, other studies suggest that high ERbeta expression is associated to a worse prognosis. Aim: to clarify some of the molecular mechanisms linking ERbeta to PC evolution by exposing the cell line CWR22Rv1 to ERbeta selective agonists. CWR22Rv1 cells mimic the natural history of PC progression because derive from a relapsed primary human androgen-dependent PC tumor (CWR22), serially xeno-transplanted in castrated nude mice; the androgen insensitivity of this cell line is due to the appearance of a constitutively active AR of 75 kDa, in addition to the wild type form (110kDa). Results: a chronic treatment (up to 12 weeks in vitro) of CWR22Rv1 with the ERbeta selective agonist diarylpropionitrile (DPN, 10-8M) results in a slight but significant decrease of the proliferation rate, which is apparent from the 5\ub0 week onward. Within the same time interval we found a significant and progressive increase of the oncosuppressor protein PTEN and of the cell cycle inhibitor p21. Moreover, DPN induces the gradually increase of the 110/75 kDa AR ratio, suggesting a partial recovery of the androgen-sensitivity. Surprisingly, DPN neither seem to activate transcription in a \u201cclassical\u201d ERE-reporter construct, nor it causes ERbeta translocation into the nucleus (as shown by immunocytochemistry). Conclusions: even though ERbeta selective agonists seem to possess antiproliferative and prodifferentiative roles in AIPC, the molecular basis of ERbeta-mediated action needs to be further evaluated. In memory of Donatella Dond