Role of estrogen receptor beta in mouse ventral prostate with relation to human prostatic diseases

Abstract

In this thesis we investigate role of estrogen receptor beta (ERbeta) in development and functioning of mouse ventral prostate, using it as a model for human extrapolations. ERbeta was discovered in 1995 and is a member of a nuclear receptors superfamily, acting as a transcription factor for steroid hormone signaling. The importance of ERbeta in the prostate emerged from the fact that ERbeta is expressed in the functional part of prostate gland prostatic epithelium. Before ERbeta discovery, estrogen signaling in the prostate considered indirect via stromal ERalpha. In our studies, we utilized comparative approach, using genetically modified mice with inactivated ERbeta (ERbeta-/-), ERalpha (ERalpha-/-) and comparing them to the wild-type littermates (Wt).

In the first study, we tried to characterize morphological properties of mouse ventral prostate in the absence of ERbeta signaling. It has been found in our lab that ERbeta seems to be antiproliferative for the mouse ventral prostate and ERbeta-/- mice sometimes showed prostatic hyperplasia. We tried to further characterize the functional role of ERbeta in the prostatic epithelium. We calculated the proliferation rate, and evaluated the apoptosis in the prostatic epithelium in the absence of ERbeta and studied the differentiation pattern of the epithelium. It turned out that in the absence of ERbeta, mouse prostatic epithelium showed increased proliferation and suppressed apoptosis. Using cytokeratine profile as a tool to characterize epitheliocytes in the various stages of differentiation, we found the altered differentiation and accumulation of incompletely differentiated cells in the absence of ERbeta. It has been concluded that ERbeta is not only antiproliferative and suppresses apoptosis, but pro-differentiative. The last observation could be applicable in designing new methods for pharmacological treatment of prostate cancer. Moreover, it can also be used as an explanation for the unexpected results of treatment with Finasteride, observed during Prostate Cancer Prevention Trial.

In the second study, we characterized the postnatal development of mouse ventral prostate, trying to clarify the phenomenon of neonatal estrogen imprinting. It has been earlier shown that imprinting occurs through ERalpha and not ERbeta. However, ERalpha is primary localized in the stroma and not epithelium of the prostate. By harvesting prostate from different ages of postnatal development of prostate, we showed that in the time-frame of 2-4 weeks of postnatal period, it is ERalpha and not ERbeta that is expressed in the prostatic epithelium. After 4th week, ERalpha is being switched to ERbeta, marking the end of proliferation and beginning of functional activation/ differentiation of epithelium. This study showed that estrogen imprinting does occur via ERalpha, but it can occur not only indirect via stromal ERalpha, but directly through ERalpha, expressed by the epithelium in a period of 2-4 weeks of postnatal life of a mouse. The results of this study can contribute to the paradigm of estrogen imprinting that might explain the input of Asian style diet in lowering the risk for prostate cancer.