There are 1,300,000 prostate biopsies performed annually that detect about 218,000 new cases of prostate cancer in the United States. Additionally, those prostate biopsies identify 115,000 independent cases of prostatic intraepithelial neoplasia (PIN) without cancer each year, representing about 9% of total cases. PIN was first described in the 1960s as 'intraductal dysplasia '. PIN features pre-existing prostatic ducts and acini lined by cytologically atypical cells, and are subdivided into low grade (LGPIN) and high grade PIN (HGPIN). The clinical significance of PIN is in its predictive value as a marker for diagnosis of prostate cancer. However, studies have shown that there are certain portions of HGPIN lesions that can remain in pre-malignant stages and do not progress to prostate cancer while others progress to advance disease. These discrepancies have prevented us from making early and accurate diagnosis and providing immediate and effective treatment for patients. They also result in significant unnecessary costs and negatively impact our healthcare system and economy. Therefore, there is an urgent need to investigate and define cellular properties of atypical cells and their molecular determinants that can promote PIN oncogenic progression to prostate cancer. The androgen signaling pathway, mediated through the androgen receptor (AR) and its ligands, testosterone and 5?ihydrotestosterone (DHT), is essential for prostate cancer initiation and progression. It has been shown that dysregulation of the androgen pathway directly contributes to prostatic oncogenic transformation and progression from PIN to prostate cancer. Intriguingly, androgen ablation can significantly reduce the prevalence and extent of PIN lesions, suggesting that the growths of atypical cells in PIN lesions are exquisitely androgen-dependent. This result also implies that androgen ablation therapy can inhibit PIN progression and may have a clinical application in preventing and reducing prostate cancer in men. However, the precise role for abnormal activation of androgen signaling in inducing oncogenic transformation during PIN initiation is largely unknown. It is also unclear why certain PIN lesions are able to progress to prostate cancer and others remain in "pre-malignant status". In this new R21 application, we will use our new AR transgenic mouse model, R26hARL/wt;Osr1-Cre mice to test our central hypothesis that abnormal activation of androgen signaling directly contributes to PIN initiation and progression and thus inhibition of androgen signaling can repress PIN development and prevent its progression to prostatic adenocarcinoma.
Two specific aims are proposed to address two important questions: 1) Are PIN initiation and progression fully androgen-dependent and can androgen ablation prevent malignant progression of PIN to prostatic adenocarcinomas? and 2) What are the cellular and molecular properties of atypical cells in PIN lesions and how does abnormal activation of androgen signaling induce PIN initiation and oncogenic progression?
Two specific aims are proposed in this new R21 application to investigate androgen signaling in the pathogenesis of prostatic intraepithelial neoplasia (PIN). Data generated from this study should lead to the development of new therapeutic strategies for preventing and treating these premalignant lesions.